- Department Head, Immunobiology
- Professor, Immunobiology
- Professor, Medicine
- Co-Director, Arizona Center on Aging
- Professor, Nutritional Sciences
- Professor, BIO5 Institute
- Professor, Genetics - GIDP
- Professor, Neuroscience - GIDP
- Ph.D. Immunology
- University of Belgrade School of Medicine, Belgrade
- Phenotypic correlates of T cell development in the thymus
- M.S. Immunology
- University of Belgrade School of Medicine, Belgrade
- Immunostimulatory properties of the Herpes Simplex Virus glycoproteins
- M.D. General Medicine
- University of Belgrade School of Medicine, Belgrade
No activities entered.
DissertationIMB 920 (Spring 2018)
Honors Independent StudyMCB 499H (Spring 2018)
Honors Independent StudyMIC 399H (Spring 2018)
Honors ThesisMCB 498H (Spring 2018)
Introduction to ResearchMCB 795A (Spring 2018)
DissertationIMB 920 (Fall 2017)
Honors Independent StudyMCB 399H (Fall 2017)
Honors Independent StudyPSIO 399H (Fall 2017)
Honors ThesisECOL 498H (Fall 2017)
Honors ThesisMCB 498H (Fall 2017)
ResearchIMB 900 (Fall 2017)
Directed RsrchMCB 492 (Spring 2017)
DissertationIMB 920 (Spring 2017)
Honors Independent StudyMCB 499H (Spring 2017)
Honors ThesisECOL 498H (Spring 2017)
Honors ThesisMCB 498H (Spring 2017)
Independent StudyMIC 499 (Spring 2017)
ResearchIMB 900 (Spring 2017)
Honors Independent StudyMCB 399H (Fall 2016)
Honors ThesisMCB 498H (Fall 2016)
ResearchIMB 900 (Fall 2016)
- Nikolich-Zugich, J., Li, G., Smithey, M. J., Rudd, B. D., & Nikolich-Zugich, J. -. (2012). Age-associated alterations in CD8α+ dendritic cells impair CD8 T-cell expansion in response to an intracellular bacterium. Aging cell, 11(6).More infoAge-associated decline in immunity to infection has been documented across multiple pathogens, yet the relative contributions of the aged priming environment and of lymphocyte-intrinsic defects remain unclear. To address the impact of the aging environment on T-cell priming, adult naïve OT-I TCR transgenic CD8 T cells, specific for the H-2Kb-restricted immunodominant OVA(257-264) epitope, were transferred into adult or old recipient mice infected with the recombinant intracellular bacterium Listeria monocytogenes carrying the chicken ovalbumin protein (Lm-OVA). We consistently found that adult OT-I CD8 expansion was reduced in aged recipient mice, and this correlated with numeric, phenotypic, and functional defects selectively affecting CD8α+ dendritic cells (DC). Following Lm-OVA infection, aged mice failed to accumulate CD8α+ DC in the spleen, and these cells expressed much lower levels of critical costimulatory molecules in the first three days following infection. Further, aged CD8α+ DC showed impaired uptake of the bacteria at very early time points following infection. Treatment of aged mice with Flt3 ligand (Flt3L) improved the number of DC present in the spleen prior to Lm-OVA infection, and improved, but did not reconstitute, OT-I expansion to Lm-OVA infection. These results suggest that age-associated changes in antigen uptake, pathogen sensing, and/or antigen presentation contribute to impaired adaptive immune responses to microbial pathogens with aging.
- Nikolich-Zugich, J., Smithey, M. J., Li, G., Venturi, V., Davenport, M. P., & Nikolich-Zugich, J. -. (2012). Lifelong persistent viral infection alters the naive T cell pool, impairing CD8 T cell immunity in late life. Journal of immunology (Baltimore, Md. : 1950), 189(11).More infoPersistent CMV infection has been associated with immune senescence. To address the causal impact of lifelong persistent viral infection on immune homeostasis and defense, we infected young mice systemically with HSV-1, murine CMV, or both viruses and studied their T cell homeostasis and function. Herpesvirus(+) mice exhibited increased all-cause mortality compared with controls. Upon Listeria-OVA infection, 23-mo-old animals that had experienced lifelong herpesvirus infections showed impaired bacterial control and CD8 T cell function, along with distinct alterations in the T cell repertoire both before and after Listeria challenge, compared with age-matched, herpesvirus-free controls. Herpesvirus infection was associated with reduced naive CD8 T cell precursors above the loss attributable to aging. Moreover, the OVA-specific CD8 T cell repertoire recruited after Listeria challenge was entirely nonoverlapping between control and herpesvirus(+) mice. To our knowledge, this study for the first time causally links lifelong herpesvirus infection to all-cause mortality in mice and to disturbances in the T cell repertoire, which themselves correspond to impaired immunity to a new infection in aging.
- Nikolich-Zugich, J., Lang, A., & Nikolich-Zugich, J. -. (2011). Functional CD8 T cell memory responding to persistent latent infection is maintained for life. Journal of immunology (Baltimore, Md. : 1950), 187(7).More infoAging is associated with depressed naive T cell responses, but it is less clear whether T cell memory established early in life also becomes impaired with age. This is particularly important for T cells responding to latent persistent infection, which need to remain functional and capable of controlling the infection over the lifetime; however, repeated stimulation over the lifetime may dysregulate their maintenance or function, potentially contributing to impaired immunity in the elderly. Systemic infection with HSV-1, a persistent latent virus, is associated with memory inflation of virus-specific CD8 T cells. We tested how these inflated memory cells are maintained from adulthood into old age. We found no significant differences in the numbers (i.e., blood, spleen), ex vivo Ag-specific IFN-γ production, and in vivo recall response to HSV-1 (i.e., proliferation, IFN-γ production, cytolysis) between adult and old memory T cells. There was a discrete shift from dominantly effector memory phenotype in the adults to a central memory-like phenotype in the old mice, with fewer old cells expressing the killer cell lectin-like receptor G1 (KLRG1). Adult and old KLRG1(+) memory CD8 T cells were functionally identical: both produced IFN-γ but could minimally proliferate in response to viral challenge. Interestingly, regardless of age, KLRG1(+) cells retained the ability to proliferate and survive in response to homeostatic signals, both in vitro (culture with IL-7 and IL-15) and in vivo (expansion following transfer into lymphopenic recipients). This finding demonstrates that functional effector memory T cells, including those expressing KLRG-1, are maintained and are functional for life, despite the presence of persistent viral infection.
- Nikolich-Zugich, J., Rudd, B. D., Venturi, V., Davenport, M. P., & Nikolich-Zugich, J. -. (2011). Evolution of the antigen-specific CD8+ TCR repertoire across the life span: evidence for clonal homogenization of the old TCR repertoire. Journal of immunology (Baltimore, Md. : 1950), 186(4).More infoDefects in T cell responses against pathogens and reduced diversity of TCRs have been described at both extremes of the life span. Yet, we still lack information on how Ag-specific T cell populations are maintained and/or altered from birth to old age. In this study, for the first time to our knowledge, we provide insight into Ag-specific TCR repertoire changes over the life span at the single-cell level. We have examined the TCR diversity of the primary CD8(+) T cell response to the immunodominant HSV-1 epitope HSV glycoprotein B 495-502 (HSV gB(498-505); SSIEFARL) (gB-8p) in neonatal, adult, and old C57BL/6 mice. The global distinctive features of the gB-8p-specific TCR repertoire were preserved in mice of different ages. However, both old and especially neonatal mice exhibited significant decreases in TCR diversity compared with that of adult mice. Still, although the neonatal Ag-specific repertoire comprised expectedly shorter germline-biased CDR3β lengths, the repertoire was surprisingly complex, and only a minority of responding cells lacked random nucleotide additions. Changes with aging included increased use of the already dominant TCRVβ10 family, a trend for lower content of the TCR containing the germline WG motif in the CDR3, and a remarkable sharing of one dominant clonotype between individual old mice, implying operation of selective mechanisms. Implications for the rational design of vaccines for neonates and the elderly are discussed.
- Nikolich-Zugich, J., Rudd, B. D., Venturi, V., Li, G., Samadder, P., Ertelt, J. M., Way, S. S., Davenport, M. P., & Nikolich-Zugich, J. -. (2011). Nonrandom attrition of the naive CD8+ T-cell pool with aging governed by T-cell receptor:pMHC interactions. Proceedings of the National Academy of Sciences of the United States of America, 108(33).More infoImmunity against new infections declines in the last quartile of life, as do numbers of naive T cells. Peripheral maintenance of naive T cells over the lifespan is necessary because their production drastically declines by puberty, a result of thymic involution. We report that this maintenance is not random in advanced aging. As numbers and diversity of naive CD8(+) T cells declined with aging, surviving cells underwent faster rates of homeostatic proliferation, were selected for high T-cell receptor:pMHC avidity, and preferentially acquired "memory-like" phenotype. These high-avidity precursors preferentially responded to infection and exhibited strong antimicrobial function. Thus, T-cell receptor avidity for self-pMHC provides a proofreading mechanism to maintain some of the fittest T cells in the otherwise crumbling naive repertoire, providing a degree of compensation for numerical and diversity defects in old T cells.
- Nikolich-Zugich, J., Smithey, M. J., Renkema, K. R., Rudd, B. D., & Nikolich-Zugich, J. -. (2011). Increased apoptosis, curtailed expansion and incomplete differentiation of CD8+ T cells combine to decrease clearance of L. monocytogenes in old mice. European journal of immunology, 41(5).More infoAging is accompanied by altered immunity, resulting in a variable state of poorly understood immunodeficiency. While both the numbers and the functionality of naïve T cells are decreased by aging, the impact of these changes upon immune defense against bacterial pathogens in vivo remains understudied. Using a model of Listeria monocytogenes (Lm), where the primary CD8(+) T-cell response is critically important for immune defense, we show that C57BL/6 (B6) mice exhibit an age-dependent reduction in survival, with delayed bacterial clearance in old animals. Kinetic analysis of antigen-specific CD8(+) T-cell expansion showed that CD8(+) effectors begin dividing at the same time in old and adult mice, but that the proliferative burst remained incomplete during discrete windows of time and was coupled with increased effector apoptosis in old mice. Further, antilisterial CD8(+) T cells in old mice showed altered expression of key phenotypic and effector molecules and diminished polyfunctionality, measured by the ability to simultaneously produce multiple effector molecules. These results suggest that defects in functional maturation of CD8(+) cells in aged mice, compounded by (or perhaps coupled to) their reduced expansion in response to infection, yield effector CD8(+) T-cell populations insufficient in size and capability to effectively clear newly encountered intracellular pathogens.
- Nikolich-Zugich, J., Uhrlaub, J. L., Brien, J. D., Widman, D. G., Mason, P. W., & Nikolich-Zugich, J. -. (2011). Repeated in vivo stimulation of T and B cell responses in old mice generates protective immunity against lethal West Nile virus encephalitis. Journal of immunology (Baltimore, Md. : 1950), 186(7).More infoOlder adults exhibit higher morbidity and mortality from infectious diseases compared with those of the general population. The introduction and rapid spread of West Nile virus (WNV) throughout the continental United States since 1999 has highlighted the challenge of protecting older adults against emerging pathogens: to this day there is no therapy or vaccine approved for human use against West Nile encephalitis. In this study, we describe the characterization of T and B cell responses in old mice after vaccination with RepliVAX WN, a novel West Nile encephalitis vaccine based on single-cycle flavivirus particles. In adult mice, RepliVAX WN induced robust and long-lasting CD4(+) and CD8(+) T cell and Ab (B cell) responses against natural WNV epitopes, similar to those elicited by primary WNV infection. Primary and memory T and B cell responses in old mice against RepliVAX WN vaccination were significantly lower than those seen in younger mice, similar to the response of old mice to infection with WNV. Surprisingly, both the quality and the quantity of the recall Ab and T cell responses in vaccinated old mice were improved to equal or exceed those in adult animals. Moreover, these responses together (but not individually) were sufficient to protect both old and adult mice from severe WNV disease upon challenge. Therefore, at least two cycles of in vivo restimulation are needed for selection and expansion of protective lymphocytes in older populations, and live, single-cycle virus vaccines that stimulate both cellular and humoral immunity can protect older individuals against severe viral disease.
- Nikolich-Zugich, J., Rudd, B. D., Venturi, V., Smithey, M. J., Way, S. S., Davenport, M. P., & Nikolich-Zugich, J. -. (2010). Diversity of the CD8+ T cell repertoire elicited against an immunodominant epitope does not depend on the context of infection. Journal of immunology (Baltimore, Md. : 1950), 184(6).More infoThe diversity of the pathogen-specific T cell repertoire is believed to be important in allowing recognition of different pathogen epitopes and their variants and thereby reducing the opportunities for mutation-driven pathogen escape. However, the extent to which the TCR repertoire can be manipulated by different vaccine strategies so as to obtain broad diversity and optimal protection is incompletely understood. We have investigated the influence of the infectious/inflammatory context on the TCR diversity of the CD8(+) T cell response specific for the immunodominant epitope in C57BL/6 mice, derived from glycoprotein B of HSV-1. To that effect, we compared TCR V segment utilization, CDR3 length, and sequence diversity of the response to natural HSV-1 infection with those elicited by either Listeria monocytogenes or vaccinia virus expressing the immunodominant epitope in C57BL/6 mice. We demonstrate that although the type of infection in which the epitope was encountered can influence the magnitude of the CD8(+) T cell responses, TCR beta-chain repertoires did not significantly differ among the three infections. These results suggest that widely different live vaccine vectors may have little impact upon the diversity of the induced CTL response, which has important implications for the design of live CTL vaccine strategies against acute and chronic infections.
- Nikolich-Zugich, J., Wertheimer, A. M., Uhrlaub, J. L., Hirsch, A., Medigeshi, G., Sprague, J., Legasse, A., Wilk, J., Wiley, C. A., Didier, P., Tesh, R. B., Murray, K. O., Axthelm, M. K., Wong, S. W., & Nikolich-Zugich, J. -. (2010). Immune response to the West Nile virus in aged non-human primates. PloS one, 5(12).More infoRisk of encephalitis from West Nile virus (WNV) infection increases dramatically with age. Understanding the basis of this susceptibility requires development of suitable animal models. Here, we investigated the immune response to WNV in old non-human primates.
- Nikolich-Zugich, J., Lang, A., Brien, J. D., & Nikolich-Zugich, J. -. (2009). Inflation and long-term maintenance of CD8 T cells responding to a latent herpesvirus depend upon establishment of latency and presence of viral antigens. Journal of immunology (Baltimore, Md. : 1950), 183(12).More infoFollowing the priming and contraction phases of the T cell response, latent persistent herpesviruses lead to an accumulation of large pools of virus-specific CD8 T cells, also known as memory inflation (MI). The mechanism of this inflation is incompletely understood, largely because the molecular reactivation of these viruses in vivo and its impact upon T cell biology have not been resolved in mice, and because the relevant observations in humans remain, by necessity, correlative. Understanding these processes is essential from the standpoint of the proposed critical role for latent herpesviruses in aging of the immune system. We studied the causes of memory CD8 T cell accumulation following systemic HSV-1 administration as a model of widespread latent viral infection in humans. A direct role of viral latency and Ag-specific restimulation in driving the accumulation and maintenance of inflated CD8 T cells and a strongly suggested role of viral reactivation in that process were shown by the following: 1) lack of MI in the absence of established latency; 2) prevention or delay of MI with drugs that curtail viral replication; and 3) abrogation of MI by the transfer of inflated T cells into a virus-free environment. These results strongly suggest that periodic, subclinical reactivations of a latent persistent virus cause dysregulation of memory CD8 T cell homeostasis, similar to the one in humans. Moreover, results with antiviral drugs suggest that this approach could be considered as a treatment modality for maintaining T cell diversity and/or function in old age.
- Nikolich-Zugich, J., & Nikolich-Zugich, J. -. (2008). Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nature reviews. Immunology, 8(7).More infoA diverse and well-balanced repertoire of T cells is thought to be crucial for the efficacious defence against infection with new or re-emerging pathogens throughout life. In the last third of the mammalian lifespan, the maintenance of a balanced T-cell repertoire becomes highly challenging because of the changes in T-cell production and consumption. In this Review, I question whether latent persistent pathogens might be key factors that drive this imbalance and whether they determine the extent of age-associated immune deficiency.
- Nikolich-Zugich, J., Rudd, B. D., Brien, J. D., Davenport, M. P., & Nikolich-Zugich, J. -. (2008). Cutting edge: TLR ligands increase TCR triggering by slowing peptide-MHC class I decay rates. Journal of immunology (Baltimore, Md. : 1950), 181(8).More infoTLR ligands are among the key stimuli driving the optimal dendritic cell (DC) maturation critical for strong and efficacious T cell priming. In this study, we show that part of this effect occurs via increased TCR triggering. Pretreatment of DCs with TLR ligands resulted in the triggering of many more TCRs in responding CD8(+) T cells. Importantly, even when DCs expressed the same amount of cognate peptide-MHC (pMHC) molecules, TLR ligand treatment resulted in down-regulation of larger numbers of TCR molecules. This was independent of the up-regulation of costimulatory, adhesion or cytokine molecules or the amount of noncognate pMHCs. Rather, DCs pretreated with TLR ligands exhibited increased stability of cognate pMHCs, enabling extended TCR triggering. These findings are of potential importance to T cell vaccination.