Two separate defects affecting true naive or virtual memory T cell precursors combine to reduce naive T cell responses with aging
Professor and Chair, Dept. of Immunobiology
Co-Director, Arizona Center on Aging
University of Arizona College of Medicine
Janko Nikolich-Zugich received his MD from Belgrade University Medical School in 1984, subsequently receiving an MSc and a PhD in Immunology from the same University. Dr. Nikolich-Zugich worked from 1987 to 1990 as a Research Associate at the Scripps Clinic and Research Foundation in the laboratory of Dr. Michael J. Bevan, FRS, NAS, HHMI. In 1990, he joined the Memorial Sloan-Kettering Cancer Center in New York as the Head of both the Flow Cytometry Core Facility and the Laboratory of T Cell Development. He served as an Assistant Professor (1990-1996) and an Associate Professor (1996-2001) at both the Cornell University Graduate School of Medical Sciences and the Division of Molecular Medicine in Cornell University School of Medicine. He was recipient of the Pew Biomedical Scholar Award and the Louise and Allston Boyer Young Scientist Award. Dr. Nikolich-Zugich moved to the Oregon Health & Science University in 2001, assuming position of Senior Scientist at the Vaccine and Gene Therapy Institute and joint appointments as a Professor (tenured) in the Department of Molecular Microbiology and Immunology and a Senior Scientist at the Oregon National Primate Research Center. He was member of the NIH Cellular and Molecular Immunology-B Study Section from 2003-2008, is member of multiple NIA and NIAID review panels, and is on the organizing or scientific committees for several international conferences and meetings. He was President of the American Aging Association in 2009-10. In 2008, Dr. Nikolich-Zugich moved to the University of Arizona to lead the Department of Immunobiology and the Arizona Center on Aging. He can be reached by e-mail at firstname.lastname@example.org.
My laboratory is interested in the biology of T lymphocytes, particularly of CD8+ cytotoxic T lymphocytes (CTL) in health, infection and aging. Our studies are performed in the context of the relationship between immune system and microorganisms (acute and persistent pathogens and normal flora) over the lifespan of the organism, with particular emphasis upon the age-related defects in immunity and defects in long-term homeostasis of the immune system.
Figure 1. Two commonly encountered defects in T-cell biology with aging. A – Defect in T-cell signal transduction upon antigen recognition. Most of the evidence suggests that this defect is cell-autonomous. B – Disruption in T-cell population balance due to thymic involution, reduced production of new naïve T-cells, their utilization and conversion into memory cells and, eventually, their excessive homeostatic proliferation. Figure from Nikolich-Zugich, J., Nat. Rev. Immunol., 2008, with evidence for excessive homeostatic proliferation from Cicin-Sain, L. et al., PNAS USA 2007.
Diagnosis of the most critical, primary defects in innate and adaptive immunity of the old age is being followed by studies to repair or modulate those defects by immune intervention as well as by tailored, rational vaccine design. Our studies are often pursued by vertical model integration - using broad and fundamental studies in rodents to crystallize questions to be asked and verified in non-human primates, leading to final and most relevant studies in humans. The main virus targets of these studies are the herpesviruses (HSV and CMV), pox (CPXV, VACV) and flaviviruses (chiefly the West Nile virus - WNV), although the research has more recently been broadened to bacteria (Listeria and Francisella).
All of our studies fall under the two broad topics: (i) understanding which T cell, particularly CD8 T cell, properties are most critical for protective immunity; and (ii) elucidating how are T cell maintained for life and why their biology is disturbed with old age. These are described in more detail below.
Cytotoxic T lymphocyte biology and antiviral activity
One main topic of research of my lab focuses is the selection, recognition, function, and homeostasis of cytotoxic T lymphocytes. We employ a combination of structural, molecular, transgenic, and functional approaches, using crystallographic modeling, TCR sequence and CDR3 length analysis, soluble and cell-bound TCR:peptide:MHC interactions, transgenesis and site-directed mutagenesis, and functional immunological assays. The emphasis of our approach is on following and manipulating the CTL response in vivo. This allows us to precisely dissect the CTL recognition, CTL repertoire and CTL activation in a setting where CTLs combat natural pathogens or cancer in the course of a lifespan of an organism.
Figure 2: Structures of the MHC class I molecules H-2Kb and H-2Kbm8, complexed to an altered peptide ligand (H2E) based upon the naturally occurring peptide from HSV-1 gB (SSIEFARL). Figure illustrates potential restoration of hydrogen bonds in the MHC pocket B, located away from the TCR contact area. Biological evidence shows that such interactions can profoundly impact T-cell recognition and immune defense, as evidenced from our prior work (Dyall, R. et al., J. Exp. Med. 1996). Figure from Miley, M.J. et al., J. Exp. Med. 2004
The projects include:
Immune senescence and its correction
Our second major interest is to understand decline of the immune function with aging, which is believed to be one of the contributing causes to the morbidity and mortality in old age. We are studying the fundamental mechanisms behind this decline in a series of studies in rodents and primates. Maintenance of T-cell repertoire diversity, T-cell homeostasis and the emergence of age-related T-cell clonal expansions (TCE) are all being studied.
Another fascinating problem is the interaction of the immune system with life-long chronic and persisting pathogens from the herpesvirus family, and the impact of this interaction upon the aging immune system. These studies should pave way for the immune reconstitution and vaccine engineering experiments that will ameliorate and treat the undesirable consequences of immune senescence.
The projects include:
Figure 3. Spectratyping (“Immunoscope”) method to assess the complexity of TCR utilization in the course of a biological process (infection, aging, homeostatic proliferation, etc.). For description of this technique, please see our prior publications (Messaoudi, I. et al., Science, 2002; Messaoudi, I. et al., J. Exp. Med., 2004).
Figure 4. Left – transmission cycle of the West Nile virus. Mosquitoes and birds are natural and primary hosts, however, the virus can infect (via mosquito bite) a wide variety of dead-end hosts. The virus is particularly dangerous to older adults over the age of 70. Right – importance of adaptive immunity in combating WNV. Rag-KO mice, which lack T and B cells, die of massive WNV infiltration and neuropathology (J. Uhrlaub, J. Brien, C. Wiley et al, unpublished).
Finally, we study the process of aging, understanding that this is a quintessential complex process which is best understood from an interdisciplinary angle and taking into account multiple cells, tissues and organs affected by it. Multidisciplinary studies on quality of organ function in metabolic manipulations of longevity are currently in progress.
Aging of the Immune System YouTube Video (51:04)- Dr. Janko Nikolich-Zugich
MD Belgrade University Medical School 1984
PhD Immunology, Belgrade University Medical School 1993
1656 E. Mabel Street
P.O. Box 245221
Tucson, AZ 85724-5221
Medical Research Building Suite 240