Developing an in-depth understanding of the factors that regulate the induction, quality, and longevity of anti- viral T cell responses is essential for devising rational strategies to combat viral infections. A hallmark of robust anti-viral immunity is the elaboration of potent CD4 and CD8 T cell responses which act cooperatively to bring about control of the infection. The consequences of ineffective responses can be catastrophic, resulting in viral persistence or the loss of long-lived immunological memory. Nevertheless, the signals which drive the development of the most robust polyfunctional effector responses and dictate the emergence of memory T cells are not fully understood. The purpose of this proposal is to capitalize on compelling preliminary findings which indicate that IL-21 plays a vital role in anti-viral immunity. Our initial studies clearly show that without sufficient levels of IL-21 the generation of polyfunctional effector CD8 T cells is compromised, and quite strikingly T cell exhaustion is exacerbated during chronic infections. Significantly, many of the phenotypic and functional impairments in anti-viral CDS T cells which manifest in the absence of IL-21 resemble the defects observed in CD4 T cell deficient hosts. A principal producer of IL-21 are CD4 follicular helper cells (Tfh) which function to help antibody responses, therefore Tfh derived IL-21 may be the critical factor that helps CD8 T cell responses. It is, however, unclear whether IL-21 is acting directly or indirectly on anti-viral CD8 T cells to promote their functionality, how T cell heterogeneity is shaped by IL-21, whether Tfh are the essential cellular sources of IL-21, and whether IL-21 based treatments have therapeutic benefits on viral control both during acute and chronic infection. We therefore propose the following specific aims: 1). Determine the direct effects of IL-21 on polyfunctional anti-viral CDS T cells. 2). Elucidate the role of CD4 T cell-derived IL-21 in promoting anti-viral immunity. 3). Define the significance of IL-21-producing CD4 T cells during viral infections of humans 4). Determine the therapeutic effects of IL-21 on anti-viral immunity and control.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI082966-05
Application #
8460850
Study Section
Special Emphasis Panel (ZAI1-BDP-I (J4))
Program Officer
Miller, Lara R
Project Start
2009-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$437,798
Indirect Cost
$138,960
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Cox, Maureen A; Kahan, Shannon M; Zajac, Allan J (2013) Anti-viral CD8 T cells and the cytokines that they love. Virology 435:157-69
Phares, Timothy W; DiSano, Krista D; Hinton, David R et al. (2013) IL-21 optimizes T cell and humoral responses in the central nervous system during viral encephalitis. J Neuroimmunol 263:43-54
Ding, Yanna; Li, Jun; Wu, Qi et al. (2013) IL-17RA is essential for optimal localization of follicular Th cells in the germinal center light zone to promote autoantibody-producing B cells. J Immunol 191:1614-24
Mollo, Sarah B; Zajac, Allan J; Harrington, Laurie E (2013) Temporal requirements for B cells in the establishment of CD4 T cell memory. J Immunol 191:6052-9
Ingram, Jennifer T; Yi, John S; Zajac, Allan J (2011) Exhausted CD8 T cells downregulate the IL-18 receptor and become unresponsive to inflammatory cytokines and bacterial co-infections. PLoS Pathog 7:e1002273
Cox, Maureen A; Harrington, Laurie E; Zajac, Allan J (2011) Cytokines and the inception of CD8 T cell responses. Trends Immunol 32:180-6
Petrelli, Alessandra; Carvello, Michele; Vergani, Andrea et al. (2011) IL-21 is an antitolerogenic cytokine of the late-phase alloimmune response. Diabetes 60:3223-34
Yi, John S; Cox, Maureen A; Zajac, Allan J (2010) T-cell exhaustion: characteristics, causes and conversion. Immunology 129:474-81
Cox, Maureen A; Zajac, Allan J (2010) Shaping successful and unsuccessful CD8 T cell responses following infection. J Biomed Biotechnol 2010:159152

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