- Assistant Professor, Immunobiology
- Member of the Graduate Faculty
- Ph.D. Genetics/Immunology
- University of Cologne, Cologne
- M.S. Biochemistry
- Free University of Berlin, Berlin
- University of Arizona, Tucson, Arizona (2013 - Ongoing)
- Yale University, New Haven, Connecticut (2011 - 2013)
- Yale University, New Haven, Connecticut (2006 - 2011)
- Center for Blood Research, Harvard University (2004 - 2005)
- Center for Blood Research, Harvard University (2001 - 2004)
- University of Cologne (1999 - 2001)
- Dana-Farber Cancer Institute, Harvard University (1996 - 1998)
- Travel Award
- American Association of Immunologists, Spring 2018
Immunology and Inflammation in Health and Disease
Innate Instruction of Adaptive Immunity
Basic and Advanced ImmunologyIMB 548 (Fall 2022)
Med Microbiology & ImmunologyIMB 401 (Spring 2022)
Med Microbiology & ImmunologyIMB 501 (Spring 2022)
Basic and Advanced ImmunologyIMB 548 (Fall 2021)
Med Microbiology & ImmunologyIMB 401 (Spring 2021)
Med Microbiology & ImmunologyIMB 501 (Spring 2021)
Basic and Advanced ImmunologyIMB 548 (Fall 2020)
Med Microbiology & ImmunologyIMB 401 (Spring 2020)
Med Microbiology & ImmunologyIMB 501 (Spring 2020)
Basic and Advanced ImmunologyIMB 548 (Fall 2019)
Honors ThesisMIC 498H (Spring 2019)
Med Microbiology & ImmunologyIMB 401 (Spring 2019)
Med Microbiology & ImmunologyIMB 501 (Spring 2019)
Scientific GrantsmanshipIMB 521 (Spring 2019)
Basic and Advanced ImmunologyIMB 548 (Fall 2018)
DissertationIMB 920 (Fall 2018)
Honors ThesisMIC 498H (Fall 2018)
Introduction to ResearchMCB 795A (Fall 2018)
DissertationIMB 920 (Spring 2018)
Honors Independent StudyMCB 499H (Spring 2018)
Honors ThesisMCB 498H (Spring 2018)
Medical Micro+ImmunologyIMB 501 (Spring 2018)
Research SeminarIMB 696A (Spring 2018)
Student SeminarCMM 696B (Spring 2018)
Basic and Advanced ImmunologyIMB 548 (Fall 2017)
Directed ResearchBIOC 392 (Fall 2017)
DissertationIMB 920 (Fall 2017)
Honors Independent StudyMCB 499H (Fall 2017)
Honors ThesisMCB 498H (Fall 2017)
Introduction to ResearchMCB 795A (Fall 2017)
Research SeminarIMB 696A (Fall 2017)
Student SeminarCMM 696B (Fall 2017)
DissertationIMB 920 (Spring 2017)
Research SeminarIMB 696A (Spring 2017)
Student SeminarCMM 696B (Spring 2017)
Basic and Advanced ImmunologyIMB 548 (Fall 2016)
DissertationIMB 920 (Fall 2016)
Honors Independent StudyMIC 399H (Fall 2016)
ResearchIMB 900 (Fall 2016)
Research SeminarIMB 696A (Fall 2016)
Student SeminarCMM 696B (Fall 2016)
ResearchIMB 900 (Spring 2016)
Research SeminarIMB 696A (Spring 2016)
Student SeminarCMM 696B (Spring 2016)
- Schenten, D., & Bhattacharya, D. (2021). Immunology of SARS-CoV-2 infections and vaccines. Advances in immunology, 151, 49-97.More infoSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections trigger viral RNA sensors such as TLR7 and RIG-I, thereby leading to production of type I interferon (IFN) and other inflammatory mediators. Expression of viral proteins in the context of this inflammation leads to stereotypical antigen-specific antibody and T cell responses that clear the virus. Immunity is then maintained through long-lived antibody-secreting plasma cells and by memory B and T cells that can initiate anamnestic responses. Each of these steps is consistent with prior knowledge of acute RNA virus infections. Yet there are certain concepts, while not entirely new, that have been resurrected by the biology of severe SARS-CoV-2 infections and deserve further attention. These include production of anti-IFN autoantibodies, early inflammatory processes that slow adaptive humoral immunity, immunodominance of antibody responses, and original antigenic sin. Moreover, multiple different vaccine platforms allow for comparisons of pathways that promote robust and durable adaptive immunity.
- Wondrak, G. T., Jandova, J., Williams, S. J., & Schenten, D. (2021). Solar simulated ultraviolet radiation inactivates HCoV-NL63 and SARS-CoV-2 coronaviruses at environmentally relevant doses. Journal of photochemistry and photobiology. B, Biology, 224, 112319.More infoThe germicidal properties of short wavelength ultraviolet C (UVC) light are well established and used to inactivate many viruses and other microbes. However, much less is known about germicidal effects of terrestrial solar UV light, confined exclusively to wavelengths in the UVA and UVB regions. Here, we have explored the sensitivity of the human coronaviruses HCoV-NL63 and SARS-CoV-2 to solar-simulated full spectrum ultraviolet light (sUV) delivered at environmentally relevant doses. First, HCoV-NL63 coronavirus inactivation by sUV-exposure was confirmed employing (i) viral plaque assays, (ii) RT-qPCR detection of viral genome replication, and (iii) infection-induced stress response gene expression array analysis. Next, a detailed dose-response relationship of SARS-CoV-2 coronavirus inactivation by sUV was elucidated, suggesting a half maximal suppression of viral infectivity at low sUV doses. Likewise, extended sUV exposure of SARS-CoV-2 blocked cellular infection as revealed by plaque assay and stress response gene expression array analysis. Moreover, comparative (HCoV-NL63 versus SARS-CoV-2) single gene expression analysis by RT-qPCR confirmed that sUV exposure blocks coronavirus-induced redox, inflammatory, and proteotoxic stress responses. Based on our findings, we estimate that solar ground level full spectrum UV light impairs coronavirus infectivity at environmentally relevant doses. Given the urgency and global scale of the unfolding SARS-CoV-2 pandemic, these prototype data suggest feasibility of solar UV-induced viral inactivation, an observation deserving further molecular exploration in more relevant exposure models.
- Wondrak, G. T., Jandova, J., Williams, S. J., & Schenten, D. (2021). Solar simulated ultraviolet radiation inactivates HCoV-NL63 and SARS-CoV-2 coronaviruses at environmentally relevant doses. bioRxiv : the preprint server for biology.More infoThe germicidal properties of short wavelength ultraviolet C (UVC) light are well established and used to inactivate many viruses and other microbes. However, much less is known about germicidal effects of terrestrial solar UV light, confined exclusively to wavelengths in the UVA and UVB regions. Here, we have explored the sensitivity of the human coronaviruses HCoV-NL63 and SARS-CoV-2 to solar-simulated full spectrum ultraviolet light (sUV) delivered at environmentally relevant doses. First, HCoV-NL63 coronavirus inactivation by sUV-exposure was confirmed employing ( ) viral plaque assays, ( ) RT-qPCR detection of viral genome replication, and ( ) infection-induced stress response gene expression array analysis. Next, a detailed dose-response relationship of SARS-CoV-2 coronavirus inactivation by sUV was elucidated, suggesting a half maximal suppression of viral infectivity at low sUV doses. Likewise, extended sUV exposure of SARS-CoV-2 blocked cellular infection as revealed by plaque assay and stress response gene expression array analysis. Moreover, comparative (HCoV-NL63 versus SARS-CoV-2) single gene expression analysis by RT-qPCR confirmed that sUV exposure blocks coronavirus-induced redox, inflammatory, and proteotoxic stress responses. Based on our findings, we estimate that solar ground level full spectrum UV light impairs coronavirus infectivity at environmentally relevant doses. Given the urgency and global scale of the unfolding SARS-CoV-2 pandemic, these prototype data suggest feasibility of solar UV-induced viral inactivation, an observation deserving further molecular exploration in more relevant exposure models.
- O'Ketch, M., Williams, S., Larson, C., Uhrlaub, J. L., Wong, R., Hall, B., Deshpande, N. R., & Schenten, D. (2020). MAVS regulates the quality of the antibody response to West-Nile Virus. PLoS pathogens, 16(10), e1009009.More infoA key difference that distinguishes viral infections from protein immunizations is the recognition of viral nucleic acids by cytosolic pattern recognition receptors (PRRs). Insights into the functions of cytosolic PRRs such as the RNA-sensing Rig-I-like receptors (RLRs) in the instruction of adaptive immunity are therefore critical to understand protective immunity to infections. West Nile virus (WNV) infection of mice deficent of RLR-signaling adaptor MAVS results in a defective adaptive immune response. While this finding suggests a role for RLRs in the instruction of adaptive immunity to WNV, it is difficult to interpret due to the high WNV viremia, associated exessive antigen loads, and pathology in the absence of a MAVS-dependent innate immune response. To overcome these limitations, we have infected MAVS-deficient (MAVSKO) mice with a single-round-of-infection mutant of West Nile virus. We show that MAVSKO mice failed to produce an effective neutralizing antibody response to WNV despite normal antibody titers against the viral WNV-E protein. This defect occurred independently of antigen loads or overt pathology. The specificity of the antibody response in infected MAVSKO mice remained unchanged and was still dominated by antibodies that bound the neutralizing lateral ridge (LR) epitope in the DIII domain of WNV-E. Instead, MAVSKO mice produced IgM antibodies, the dominant isotype controlling primary WNV infection, with lower affinity for the DIII domain. Our findings suggest that RLR-dependent signals are important for the quality of the humoral immune response to WNV.
- O'Ketch, M., Larson, C., Williams, S., Uhrlaub, J. L., Wong, R., Deshpande, N. R., & Schenten, D. (2019). MAVS regulates the quality of the antibody response to West-Nile Virus. BioRXiv. doi:10.1101/2019.12.15.875906
- Heger, K., Fierens, K., Vahl, J. C., Aszodi, A., Peschke, K., Schenten, D., Hammad, H., Beyaert, R., Saur, D., van Loo, G., Roers, A., Lambrecht, B. N., Kool, M., & Schmidt-Supprian, M. (2014). A20-deficient mast cells exacerbate inflammatory responses in vivo. PLoS biology, 12(1), e1001762.More infoMast cells are implicated in the pathogenesis of inflammatory and autoimmune diseases. However, this notion based on studies in mast cell-deficient mice is controversial. We therefore established an in vivo model for hyperactive mast cells by specifically ablating the NF-κB negative feedback regulator A20. While A20 deficiency did not affect mast cell degranulation, it resulted in amplified pro-inflammatory responses downstream of IgE/FcεRI, TLRs, IL-1R, and IL-33R. As a consequence house dust mite- and IL-33-driven lung inflammation, late phase cutaneous anaphylaxis, and collagen-induced arthritis were aggravated, in contrast to experimental autoimmune encephalomyelitis and immediate anaphylaxis. Our results provide in vivo evidence that hyperactive mast cells can exacerbate inflammatory disorders and define diseases that might benefit from therapeutic intervention with mast cell function.
- Nish, S. A., Schenten, D., Wunderlich, F. T., Pope, S. D., Gao, Y., Hoshi, N., Yu, S., Yan, X., Lee, H. K., Pasman, L., Brodsky, I., Yordy, B., Zhao, H., Brüning, J., & Medzhitov, R. (2014). T cell-intrinsic role of IL-6 signaling in primary and memory responses. eLife, 3, e01949.More infoInnate immune recognition is critical for the induction of adaptive immune responses; however the underlying mechanisms remain incompletely understood. In this study, we demonstrate that T cell-specific deletion of the IL-6 receptor α chain (IL-6Rα) results in impaired Th1 and Th17 T cell responses in vivo, and a defect in Tfh function. Depletion of Tregs in these mice rescued the Th1 but not the Th17 response. Our data suggest that IL-6 signaling in effector T cells is required to overcome Treg-mediated suppression in vivo. We show that IL-6 cooperates with IL-1β to block the suppressive effect of Tregs on CD4(+) T cells, at least in part by controlling their responsiveness to IL-2. In addition, although IL-6Rα-deficient T cells mount normal primary Th1 responses in the absence of Tregs, they fail to mature into functional memory cells, demonstrating a key role for IL-6 in CD4(+) T cell memory formation.DOI: http://dx.doi.org/10.7554/eLife.01949.001.
- Pickard, J. M., Maurice, C. F., Kinnebrew, M. A., Abt, M. C., Schenten, D., Golovkina, T. V., Bogatyrev, S. R., Ismagilov, R. F., Pamer, E. G., Turnbaugh, P. J., & Chervonsky, A. V. (2014). Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. Nature, 514(7524), 638-41.More infoSystemic infection induces conserved physiological responses that include both resistance and 'tolerance of infection' mechanisms. Temporary anorexia associated with an infection is often beneficial, reallocating energy from food foraging towards resistance to infection or depriving pathogens of nutrients. However, it imposes a stress on intestinal commensals, as they also experience reduced substrate availability; this affects host fitness owing to the loss of caloric intake and colonization resistance (protection from additional infections). We hypothesized that the host might utilize internal resources to support the gut microbiota during the acute phase of the disease. Here we show that systemic exposure to Toll-like receptor (TLR) ligands causes rapid α(1,2)-fucosylation of small intestine epithelial cells (IECs) in mice, which requires the sensing of TLR agonists, as well as the production of interleukin (IL)-23 by dendritic cells, activation of innate lymphoid cells and expression of fucosyltransferase 2 (Fut2) by IL-22-stimulated IECs. Fucosylated proteins are shed into the lumen and fucose is liberated and metabolized by the gut microbiota, as shown by reporter bacteria and community-wide analysis of microbial gene expression. Fucose affects the expression of microbial metabolic pathways and reduces the expression of bacterial virulence genes. It also improves host tolerance of the mild pathogen Citrobacter rodentium. Thus, rapid IEC fucosylation appears to be a protective mechanism that utilizes the host's resources to maintain host-microbial interactions during pathogen-induced stress.
- Schenten, D., Nish, S. A., Yu, S., Yan, X., Lee, H. K., Brodsky, I., Pasman, L., Yordy, B., Wunderlich, F. T., Brüning, J. C., Zhao, H., & Medzhitov, R. (2014). Signaling through the adaptor molecule MyD88 in CD4+ T cells is required to overcome suppression by regulatory T cells. Immunity, 40(1), 78-90.More infoInnate immune recognition controls adaptive immune responses through multiple mechanisms. The MyD88 signaling adaptor operates in many cell types downstream of Toll-like receptors (TLRs) and interleukin-1 (IL-1) receptor family members. Cell-type-specific functions of MyD88 signaling remain poorly characterized. Here, we have shown that the T cell-specific ablation of MyD88 in mice impairs not only T helper 17 (Th17) cell responses, but also Th1 cell responses. MyD88 relayed signals of TLR-induced IL-1, which became dispensable for Th1 cell responses in the absence of T regulatory (Treg) cells. Treg cell-specific ablation of MyD88 had no effect, suggesting that IL-1 acts on naive CD4(+) T cells instead of Treg cells themselves. Together, these findings demonstrate that IL-1 renders naive CD4(+) T cells refractory to Treg cell-mediated suppression in order to allow their differentiation into Th1 cells. In addition, IL-1 was also important for the generation of functional CD4(+) memory T cells.
- Palm, N. W., Rosenstein, R. K., Yu, S., Schenten, D. D., Florsheim, E., & Medzhitov, R. (2013). Bee venom phospholipase A2 induces a primary type 2 response that is dependent on the receptor ST2 and confers protective immunity. Immunity, 39(5), 976-85.More infoVenoms consist of toxic components that are delivered to their victims via bites or stings. Venoms also represent a major class of allergens in humans. Phospholipase A2 (PLA2) is a conserved component of venoms from multiple species and is the major allergen in bee venom. Here we examined how bee venom PLA2 is sensed by the innate immune system and induces a type 2 immune response in mice. We found that bee venom PLA2 induced a T helper type 2 (Th2) cell-type response and group 2 innate lymphoid cell activation via the enzymatic cleavage of membrane phospholipids and release of interleukin-33. Furthermore, we showed that the IgE response to PLA2 could protect mice from future challenge with a near-lethal dose of PLA2. These data suggest that the innate immune system can detect the activity of a conserved component of venoms and induce a protective immune response against a venom toxin.
- Teichmann, L. L., Schenten, D., Medzhitov, R., Kashgarian, M., & Shlomchik, M. J. (2013). Signals via the adaptor MyD88 in B cells and DCs make distinct and synergistic contributions to immune activation and tissue damage in lupus. Immunity, 38(3), 528-40.More infoDetection of self nucleic acids by Toll-like receptors (TLR) preciptates autoimmune diseases, including systemic lupus erythematosus (SLE). It remains unknown how TLR signals in specific cell types contribute to distinct manifestations of SLE. Here, we demonstrate that formation of anti-nuclear antibodies in MRL.Fas(lpr) mice entirely depends on the TLR signaling adaptor MyD88 in B cells. Further, MyD88 deficiency in B cells ameliorated nephritis, including antibody-independent interstitial T cell infiltrates, suggesting that nucleic acid-specific B cells activate nephrotoxic T cells. Surprisingly, MyD88 deletion in dendritic cells (DCs) did not affect nephritis, despite the importance of DCs in renal inflammation. In contrast, MyD88 in DCs was critical for dermatitis, revealing a separate pathogenetic mechanism. DC-expressed MyD88 promoted interferon-α production by plasmacytoid DCs, which was associated with Death domain-associated protein 6 upregulation and B lymphopenia. Our findings thus reveal unique immunopathological consequences of MyD88 signaling in B cells and DCs in lupus.
- Cataisson, C., Salcedo, R., Hakim, S., Moffitt, B. A., Wright, L., Yi, M., Stephens, R., Dai, R., Lyakh, L., Schenten, D., Yuspa, H. S., & Trinchieri, G. (2012). IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis. The Journal of experimental medicine, 209(9), 1689-702.More infoConstitutively active RAS plays a central role in the development of human cancer and is sufficient to induce tumors in two-stage skin carcinogenesis. RAS-mediated tumor formation is commonly associated with up-regulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. In this study, we report that mice lacking IL-1R or MyD88 are less sensitive to topical skin carcinogenesis than their respective wild-type (WT) controls. MyD88(-/-) or IL-1R(-/-) keratinocytes expressing oncogenic RAS are hyperproliferative and fail to up-regulate proinflammatory genes or down-regulate differentiation markers characteristic of RAS-expressing WT keratinocytes. Although RAS-expressing MyD88(-/-) keratinocytes form only a few small tumors in orthotopic grafts, IL-1R-deficient RAS-expressing keratinocytes retain the ability to form tumors in orthotopic grafts. Using both genetic and pharmacological approaches, we find that the differentiation and proinflammatory effects of oncogenic RAS in keratinocytes require the establishment of an autocrine loop through IL-1α, IL-1R, and MyD88 leading to phosphorylation of IκBα and NF-κB activation. Blocking IL-1α-mediated NF-κB activation in RAS-expressing WT keratinocytes reverses the differentiation defect and inhibits proinflammatory gene expression. Collectively, these results demonstrate that MyD88 exerts a cell-intrinsic function in RAS-mediated transformation of keratinocytes.
- Haley, K., Igyártó, B. Z., Ortner, D., Bobr, A., Kashem, S., Schenten, D., & Kaplan, D. H. (2012). Langerhans cells require MyD88-dependent signals for Candida albicans response but not for contact hypersensitivity or migration. Journal of immunology (Baltimore, Md. : 1950), 188(9), 4334-9.More infoLangerhans cells (LC) are a subset of skin-resident dendritic cells (DC) that reside in the epidermis as immature DC, where they acquire Ag. A key step in the life cycle of LC is their activation into mature DC in response to various stimuli, including epicutaneous sensitization with hapten and skin infection with Candida albicans. Mature LC migrate to the skin-draining LN, where they present Ag to CD4 T cells and modulate the adaptive immune response. LC migration is thought to require the direct action of IL-1β and IL-18 on LC. In addition, TLR ligands are present in C. albicans, and hapten sensitization produces endogenous TLR ligands. Both could contribute to LC activation. We generated Langerin-Cre MyD88(fl) mice in which LC are insensitive to IL-1 family members and most TLR ligands. LC migration in the steady state, after hapten sensitization and postinfection with C. albicans, was unaffected. Contact hypersensitivity in Langerin-Cre MyD88(fl) mice was similarly unaffected. Interestingly, in response to C. albicans infection, these mice displayed reduced proliferation of Ag-specific CD4 T cells and defective Th17 subset differentiation. Surface expression of costimulatory molecules was intact on LC, but expression of IL-1β, IL-6, and IL-23 was reduced. Thus, sensitivity to MyD88-dependent signals is not required for LC migration, but is required for the full activation and function of LC in the setting of fungal infection.
- Hoshi, N., Schenten, D., Nish, S. A., Walther, Z., Gagliani, N., Flavell, R. A., Reizis, B., Shen, Z., Fox, J. G., Iwasaki, A., & Medzhitov, R. (2012). MyD88 signalling in colonic mononuclear phagocytes drives colitis in IL-10-deficient mice. Nature communications, 3, 1120.More infoCommensal bacterial sensing by Toll-like receptors is critical for maintaining intestinal homeostasis, but can lead to colitis in the absence of interleukin-10. Although Toll-like receptors are expressed in multiple cell types in the colon, the cell type(s) responsible for the development of colitis are currently unknown. Here we generated mice that are selectively deficient in MyD88 in various cellular compartments in an interleukin-10(-/-) setting. Although epithelial expression of MyD88 was dispensable, MyD88 expression in the mononuclear phagocyte compartment was required for colitis development. Specifically, phenotypically distinct populations of colonic mononuclear phagocytes expressed high levels of interleukin-1β, interleukin-23 and interleukin-6, and promoted T-helper 17 responses in the absence of interleukin-10. Thus, gut bacterial sensing through MyD88 in mononuclear phagocytes drives inflammatory bowel disease when unopposed by interleukin-10.
- Saribasak, H., Maul, R. W., Cao, Z., Yang, W. W., Schenten, D., Kracker, S., & Gearhart, P. J. (2012). DNA polymerase ζ generates tandem mutations in immunoglobulin variable regions. The Journal of experimental medicine, 209(6), 1075-81.More infoLow-fidelity DNA polymerases introduce nucleotide substitutions in immunoglobulin variable regions during somatic hypermutation. Although DNA polymerase (pol) η is the major low-fidelity polymerase, other DNA polymerases may also contribute. Existing data are contradictory as to whether pol ζ is involved. We reasoned that the presence of pol η may mask the contribution of pol ζ, and therefore we generated mice deficient for pol η and heterozygous for pol ζ. The frequency and spectra of hypermutation was unaltered between Polζ(+/-) Polη(-/-) and Polζ(+/+) Polη(-/-) clones. However, there was a decrease in tandem double-base substitutions in Polζ(+/-) Polη(-/-) cells compared with Polζ(+/+) Polη(-/-) cells, suggesting that pol ζ generates tandem mutations. Contiguous mutations are consistent with the biochemical property of pol ζ to extend a mismatch with a second mutation. The presence of this unique signature implies that pol ζ contributes to mutational synthesis in vivo. Additionally, data on tandem mutations from wild type, Polζ(+/-), Polζ(-/-), Ung(-/-), Msh2(-/-), Msh6(-/-), and Ung(-/-) Msh2(-/-) clones suggest that pol ζ may function in the MSH2-MSH6 pathway.
- Song, Y., Shen, H., Schenten, D., Shan, P., Lee, P. J., & Goldstein, D. R. (2012). Aging enhances the basal production of IL-6 and CCL2 in vascular smooth muscle cells. Arteriosclerosis, thrombosis, and vascular biology, 32(1), 103-9.More infoIncreased circulating cytokine levels are a prominent feature of aging that may contribute to atherosclerosis. However, the role vascular cells play in chronic inflammation induced by aging is not clear. Here, we examined the role of aging on inflammatory responses of vascular cells.
- Chu, Y., Vahl, J. C., Kumar, D., Heger, K., Bertossi, A., Wójtowicz, E., Soberon, V., Schenten, D., Mack, B., Reutelshöfer, M., Beyaert, R., Amann, K., van Loo, G., & Schmidt-Supprian, M. (2011). B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice. Blood, 117(7), 2227-36.More infoThe ubiquitin-editing enzyme A20/TNFAIP3 is essential for controlling signals inducing the activation of nuclear factor-κB transcription factors. Polymorphisms and mutations in the TNFAIP3 gene are linked to various human autoimmune conditions, and inactivation of A20 is a frequent event in human B-cell lymphomas characterized by constitutive nuclear factor-κB activity. Through B cell-specific ablation in the mouse, we show here that A20 is required for the normal differentiation of the marginal zone B and B1 cell subsets. However, loss of A20 in B cells lowers their activation threshold and enhances proliferation and survival in a gene-dose-dependent fashion. Through the expression of proinflammatory cytokines, most notably interleukin-6, A20-deficient B cells trigger a progressive inflammatory reaction in naive mice characterized by the expansion of myeloid cells, effector-type T cells, and regulatory T cells. This culminates in old mice in an autoimmune syndrome characterized by splenomegaly, plasma cell hyperplasia, and the presence of class-switched, tissue-specific autoantibodies.
- Schenten, D., & Medzhitov, R. (2011). The control of adaptive immune responses by the innate immune system. Advances in immunology, 109, 87-124.More infoThe mammalian immune system comprises an adaptive and an innate component. The innate immune system employs a limited number of germ-line-encoded pattern-recognition receptors (PRRs) that recognize invariant pathogen-associated molecular patterns (PAMPs). In contrast, the adaptive immune system depends on the generation of a diverse repertoire of antigen receptors on T and B lymphocytes and subsequent activation and clonal expansion of cells carrying the appropriate antigen-specific receptors. Induction of adaptive immunity not only depends on direct antigen recognition by the antigen receptors but also relies on essential signals that are delivered by the innate immune system. In recent years, we have witnessed the discovery of a still expanding array of different PRR systems that govern the generation of adaptive immunity. Here, we review our current understanding of innate control of adaptive immunity. In particular, we discuss how PRRs initiate adaptive immune responses in general, discuss specific mechanisms that shape the ensuing T and B cell responses, and highlight open questions that are still awaiting answers.
- Kleinridders, A., Schenten, D., Könner, A. C., Belgardt, B. F., Mauer, J., Okamura, T., Wunderlich, F. T., Medzhitov, R., & Brüning, J. C. (2009). MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell metabolism, 10(4), 249-59.More infoObesity-associated activation of inflammatory pathways represents a key step in the development of insulin resistance in peripheral organs, partially via activation of TLR4 signaling by fatty acids. Here, we demonstrate that palmitate acting in the central nervous system (CNS) inhibits leptin-induced anorexia and Stat3 activation. To determine the functional significance of TLR signaling in the CNS in the development of leptin resistance and diet-induced obesity in vivo, we have characterized mice deficient for the TLR adaptor molecule MyD88 in the CNS (MyD88(DeltaCNS)). Compared to control mice, MyD88(DeltaCNS) mice are protected from high-fat diet (HFD)-induced weight gain, from the development of HFD-induced leptin resistance, and from the induction of leptin resistance by acute central application of palmitate. Moreover, CNS-restricted MyD88 deletion protects from HFD- and icv palmitate-induced impairment of peripheral glucose metabolism. Thus, we define neuronal MyD88-dependent signaling as a key regulator of diet-induced leptin and insulin resistance in vivo.
- Schenten, D., Kracker, S., Esposito, G., Franco, S., Klein, U., Murphy, M., Alt, F. W., & Rajewsky, K. (2009). Pol zeta ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair, and genome stability. The Journal of experimental medicine, 206(2), 477-90.More infoPol zeta is an error-prone DNA polymerase that is critical for embryonic development and maintenance of genome stability. To analyze its suggested role in somatic hypermutation (SHM) and possible contribution to DNA double-strand break (DSB) repair in class switch recombination (CSR), we ablated Rev3, the catalytic subunit of Pol zeta, selectively in mature B cells in vivo. The frequency of somatic mutation was reduced in the mutant cells but the pattern of SHM was unaffected. Rev3-deficient B cells also exhibited pronounced chromosomal instability and impaired proliferation capacity. Although the data thus argue against a direct role of Pol zeta in SHM, Pol zeta deficiency directly interfered with CSR in that activated Rev3-deficient B cells exhibited a reduced efficiency of CSR and an increased frequency of DNA breaks in the immunoglobulin H locus. Based on our results, we suggest a nonredundant role of Pol zeta in DNA DSB repair through nonhomologous end joining.
- Schenten, D., Egert, A., Pasparakis, M., & Rajewsky, K. (2006). M17, a gene specific for germinal center (GC) B cells and a prognostic marker for GC B-cell lymphomas, is dispensable for the GC reaction in mice. Blood, 107(12), 4849-56.More infoIn T-cell-dependent antibody responses, antigen-specific B cells undergo a phase of secondary antibody diversification in germinal centers (GCs). Somatic hypermutation (SHM) introduces mutations into the rearranged immunoglobulin (Ig) variable (V) region genes, and class-switch recombination (CSR) alters the Ig heavy (H) chain constant region. Aberrant SHM or CSR is thought to contribute to the development of GC-derived B-cell malignancies. Diffuse large B-cell lymphomas (DLBCLs) are a heterogeneous group of such GC-derived tumors. Based on their gene expression profile, DLBCLs can be divided into activated B-cell-like and GC-like subgroups. The human gene HGAL is predominantly expressed in GCs. It is also part of the gene expression signature of GC-like DLBCL, and its high expression in DLBCL has been associated with a better clinical prognosis. We have generated mice deficient of the HGAL homologue M17 in order to investigate its functional significance. The mutant animals form normal GCs, undergo efficient CSR and SHM, and mount T-cell-dependent antibody responses similar to wild-type controls. Thus, M17 is dispensable for the GC reaction, and its potential function in the pathogenesis of DLBCL remains elusive.
- Schenten, D., Gerlach, V. L., Guo, C., Velasco-Miguel, S., Hladik, C. L., White, C. L., Friedberg, E. C., Rajewsky, K., & Esposito, G. (2002). DNA polymerase kappa deficiency does not affect somatic hypermutation in mice. European journal of immunology, 32(11), 3152-60.More infoSomatic hypermutation (SH) in B cells undergoing T cell-dependent immune responses generates high-affinity antibodies that provide protective immunity. Most current models of SH postulate the introduction of a nick into the DNA and subsequent replication-independent, error-prone short-patch synthesis by one or more DNA polymerases. The Pol kappa (DinB1) gene encodes a specialized mammalian DNA polymerase called DNA polymerase kappa (pol kappa), a member of the recently discovered Y family of DNA polymerases. The mouse PolK gene is expressed at high levels in the seminiferous tubules of the testis and in the adrenal cortex, and at lower levels in most other cells of the body including B lymphocytes. In vitro studies showed that pol kappa can act as an error-prone polymerase, although they failed to ascribe a clear function to this enzyme. The ability of pol kappa to generate mutations when extending primers on undamaged DNA templates identifies this enzyme as a potential candidate for the introduction of nucleotide changes in the immunoglobulin (Ig) genes during the process of SH. Here we show that pol kappa-deficient mice are viable, fertile and able to mount a normal immune response to the antigen (4-hydroxy-3-nitrophenyl)acetyl-chicken gamma-globulin (NP-GC). They also mutate their Ig genes normally. However, pol kappa-deficient embryonic fibroblasts are abnormally sensitive to killing following exposure to ultraviolet (UV) radiation, suggesting a role of pol kappa in translesion DNA synthesis.
- Bannert, N., Schenten, D., Craig, S., & Sodroski, J. (2000). The level of CD4 expression limits infection of primary rhesus monkey macrophages by a T-tropic simian immunodeficiency virus and macrophagetropic human immunodeficiency viruses. Journal of virology, 74(23), 10984-93.More infoThe entry of primate immunodeficiency viruses into cells is dependent on the interaction of the viral envelope glycoproteins with receptors, CD4, and specific members of the chemokine receptor family. Although in many cases the tropism of these viruses is explained by the qualitative pattern of coreceptor expression, several instances have been observed where the expression of a coreceptor on the cell surface is not sufficient to allow infection by a virus that successfully utilizes the coreceptor in a different context. For example, both the T-tropic simian immunodeficiency virus (SIV) SIVmac239 and the macrophagetropic (M-tropic) SIVmac316 can utilize CD4 and CCR5 as coreceptors, and both viruses can infect primary T lymphocytes, yet only SIVmac316 can efficiently infect CCR5-expressing primary macrophages from rhesus monkeys. Likewise, M-tropic strains of human immunodeficiency virus type 1 (HIV-1) do not infect primary rhesus monkey macrophages efficiently. Here we show that the basis of this restriction is the low level of CD4 on the surface of these cells. Overexpression of human or rhesus monkey CD4 in primary rhesus monkey macrophages allowed infection by both T-tropic and M-tropic SIV and by primary M-tropic HIV-1. By contrast, CCR5 overexpression did not specifically compensate for the inefficient infection of primary monkey macrophages by T-tropic SIV or M-tropic HIV-1. Apparently, the limited ability of these viruses to utilize a low density of CD4 for target cell entry accounts for the restriction of these viruses in primary rhesus monkey macrophages.
- Etemad-Moghadam, B., Sun, Y., Nicholson, E. K., Karlsson, G. B., Schenten, D., & Sodroski, J. (1999). Determinants of neutralization resistance in the envelope glycoproteins of a simian-human immunodeficiency virus passaged in vivo. Journal of virology, 73(10), 8873-9.More infoIn vivo passage of a simian-human immunodeficiency virus (SHIV-89.6) generated a virus, SHIV-89.6P, that exhibited increased resistance to some neutralizing antibodies (G. B. Karlsson et al., J. Exp. Med. 188:1159-1171, 1998). Here we examine the range of human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies to which the passaged virus became resistant and identify envelope glycoprotein determinants of antibody resistance. Compared with the envelope glycoproteins derived from the parental SHIV-89.6, the envelope glycoproteins of the passaged virus were resistant to antibodies directed against the gp120 V3 variable loop and the CD4 binding site. By contrast, both viral envelope glycoproteins were equally sensitive to neutralization by two antibodies, 2G12 and 2F5, that recognize poorly immunogenic structures on gp120 and gp41, respectively. Changes in the V2 and V3 variable loops of gp120 were necessary and sufficient for full resistance to the IgG1b12 antibody, which is directed against the CD4 binding site. Changes in the V3 loop specified complete resistance to a V3 loop-directed antibody, while changes in the V1/V2 loops conferred partial resistance to this antibody. The epitopes of the neutralizing antibodies were not disrupted by the resistance-associated changes. These results indicate that in vivo selection occurs for HIV-1 envelope glycoproteins with variable loop conformations that restrict the access of antibodies to immunogenic neutralization epitopes.
- Schenten, D., Marcon, L., Karlsson, G. B., Parolin, C., Kodama, T., Gerard, N., & Sodroski, J. (1999). Effects of soluble CD4 on simian immunodeficiency virus infection of CD4-positive and CD4-negative cells. Journal of virology, 73(7), 5373-80.More infoA soluble form of the CD4 receptor (sCD4) can either enhance or inhibit the infection of cells by simian immunodeficiency virus (SIV) and human immunodeficiency virus. We investigated the basis for these varying effects by studying the entry of three SIV isolates into CD4-positive and CD4-negative cells expressing different chemokine receptors. Infection of CD4-negative cells depended upon the viral envelope glycoproteins and upon the chemokine receptor, with CCR5 and gpr15 being more efficient than STRL33. Likewise, enhancement of infection by sCD4 was observed when CCR5- and gpr15-expressing target cells were used but not when those expressing STRL33 were used. The sCD4-mediated enhancement of virus infection of CD4-negative, CCR5-positive cells was related to the sCD4-induced increase in binding of the viral gp120 envelope glycoprotein to CCR5. Inhibitory effects of sCD4 could largely be explained by competition for virus attachment to cellular CD4 rather than other detrimental effects on virus infectivity (e.g., disruption of the envelope glycoprotein spike). Consistent with this, the sCD4-activated SIV envelope glycoprotein intermediate on the virus was long-lived. Thus, the net effect of sCD4 on SIV infectivity appears to depend upon the degree of enhancement of chemokine receptor binding and upon the efficiency of competition for cellular CD4.
- Etemad-Moghadam, B., Karlsson, G. B., Halloran, M., Sun, Y., Schenten, D., Fernandes, M., Letvin, N. L., & Sodroski, J. (1998). Characterization of simian-human immunodeficiency virus envelope glycoprotein epitopes recognized by neutralizing antibodies from infected monkeys. Journal of virology, 72(10), 8437-45.More infoWe characterized human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein epitopes recognized by neutralizing antibodies from monkeys recently infected by molecularly cloned simian-human immunodeficiency virus (SHIV) variants. The early neutralizing antibody response in each infected animal was directed mainly against a single epitope. This primary neutralizing epitope, however, differed among individual monkeys infected by identical viruses. Two such neutralization epitopes were determined by sequences in the V2 and V3 loops of the gp120 envelope glycoprotein, while a third neutralization epitope, apparently discontinuous, was determined by both V2 and V3 sequences. These results indicate that the early neutralizing antibody response in SHIV-infected monkeys is monospecific and directed against epitopes composed of the gp120 V2 and V3 variable loops.
- Karlsson, G. B., Halloran, M., Schenten, D., Lee, J., Racz, P., Tenner-Racz, K., Manola, J., Gelman, R., Etemad-Moghadam, B., Desjardins, E., Wyatt, R., Gerard, N. P., Marcon, L., Margolin, D., Fanton, J., Axthelm, M. K., Letvin, N. L., & Sodroski, J. (1998). The envelope glycoprotein ectodomains determine the efficiency of CD4+ T lymphocyte depletion in simian-human immunodeficiency virus-infected macaques. The Journal of experimental medicine, 188(6), 1159-71.More infoCD4+ T lymphocyte depletion in human immunodeficiency virus type 1 (HIV-1)-infected humans underlies the development of acquired immune deficiency syndrome. Using a model in which rhesus macaques were infected with chimeric simian-human immunodeficiency viruses (SHIVs), we show that both the level of viremia and the structure of the HIV-1 envelope glycoprotein ectodomains individually contributed to the efficiency with which CD4(+) T lymphocytes were depleted. The envelope glycoproteins of recombinant SHIVs that efficiently caused loss of CD4(+) T lymphocytes exhibited increased chemokine receptor binding and membrane-fusing capacity compared with those of less pathogenic viruses. These studies identify the HIV-1 envelope glycoprotein ectodomains as determinants of CD4(+) T lymphocyte loss in vivo and provide a foundation for studying pathogenic mechanisms.
- Schenten, D. (2019, August). Innate Regulation of Humoral Immunity to West Nile Virus. Infectious Disease Grand Rounds. Tucson, AZ: Division of Infectious Disease, Department of Medicine, University of Arizona College of Medicine Tucson.
- Schenten, D. (2019, December). Innate regulation of adaptive immunity to viral infections - lessons for cancer immunology. Developing Therapeutics for Cancer and Immunology. Phoenix, AZ: Arizona State University/University of Arizona.
- Schenten, D. (2019, January). Quality Control of Humoral Immunity by the Innate Signaling Adaptor MAVS. Talk, Midwinter Conference of Immunologist. Pacific Grove: Midwinter Conference of Immunologist.
- Schenten, D. (2019, July). Quality control of humoral immunity by the innate singling adaptor MAVS. Twenty Years of Philosophy and Science Conference. Lakeville, CT: Yale University.
- Schenten, D. (2019, May). Quality Control of Humoral Immunity by the Innate Signaling Adaptor MAVS. Immunology 2019. San Diego, CA: American Association of Immunologists.
- Schenten, D. (2019, September). Innate Control Mechanisms of Adaptive Immunity. Seminar, University Animal Care. Tucson, AZ: University Animal Care, University of Arizona.
- Schenten, D. (2019, September). Quality control of humoral immunity by the innate singling adaptor MAVS. ABBS Retreat. Oracle, AZ: University of Arizona.
- Schenten, D. (2018, February). Regulation of intestinal carcinogenesis by the innate signaling adaptor MAVS. Seminar, Cancer Biology Program. Tucson: UA COM.
- Schenten, D. (2017, December). Innate immune regulation in intestinal carcinogenesis. Seminar, UACC Cancer Immunotherapy Mini Symposium. Tucson, AZ: UACC.
- Schenten, D. (2017, October). Innate Control of Humoral Immunity. Invited Speaker, Seminar, Max Planck Institute, Cologne, Germany. Cologne, Germany: Max Planck Institute.
- Schenten, D. (2016, Spring). Innate Control of CD4 T Cell Responses. Seminar. Manchester, UK: University of Manchester.
- Schenten, D. (2016, Spring). Innate checkpoint control of CD4 T cell responses. Cancer Immunotherapy Seminar Series. Tucson, AZ: University of Arizona Cancer Center.
- Schenten, D. (2015, February 13). Innate Regulation of Adaptive Immunity - An overview. Skin Cancer Retreat. Tucson: University of Arizona - Cancer Center.
- Schenten, D. (2015, October 30). Mechanisms of innate control of adaptive immunity. IMB-DMI Imaging Retreat. Tucson: University of Arizona (IMB/DMI).
- Schenten, D. (2014, August). Innate Control of CD4 T cell responses. Invited Speaker, Max-Delbrueck Center for Molecular Medicine, Berlin, Germany. Berlin, Germany: Max-Delbrueck Center for Molecular Medicine.
- Schenten, D. (2014, December). The Role of TLR-induced IL-1 and IL-6 in the Control of Adaptive Immunity. Invited Speaker, BMS, UA College of Medicine - Phoenix. Phoenix: University of Arizona.
- Mastrud, N., & Schenten, D. (2019, November). The function of Il-1 family members in the regulation of Th2 immunity. Annual Biomedical Research Conference for Minority Students (ABRCMS). Anaheim, CA: American Scociety for Microbiology.
- O'Ketch, M., Larson, C., Hall, B., & Schenten, D. (2019, January). Quality Control of Humoral Immunity by the Innate Signaling Adaptor MAVS. Midwinter Conference of Immunologists. Pacific Grove, CA.
- O'Ketch, M., Larson, C., Hall, B., & Schenten, D. (2019, May). The innate signaling adaptor MAVS regulates the quality of the antibody response to West Nile Virus. Immunology 2019. San Diego, CA: AAI.
- Schenten, D., & O'Ketch, M. (2018, January 2018). MAVS, the signaling adaptor of Rig-I-like receptors, directly regulates humoral immunity to West Nile Virus. Mid-Winter Conference of Immunologists. Pacific Grove, CA.
- Schenten, D., & O'Ketch, M. (2018, Spring). MAVS, the signaling adaptor of Rig-I-like receptors, directly regulates humoral immunity to West Nile Virus. Immunology 2018. Austin, TX: American Asociation of Immunologists.
- Schenten, D. (2017, September). Rig-I-like receptors (RLRs) directly regulate humoral immunity to West Nile Virus. 19th International Conference on Lymphatic Tissues and Germinal Centers in Immune Reactions. Venice, Italy: IFOM - The FIRC Institute of Molecular Oncology.