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Multigenic Regulation of the Shutdown of Immune Responses

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Multigenic Regulation of the Shutdown of Immune Responses
Weant, Ashley
The goal of the work presented here was to determine if blocking cell death could affect the shutdown of immune responses by generating increased numbers of antigen-specific memory CD8+ T cells. During acute viral infection, large numbers of effector CD8+ T cells are generated. Following viral clearance, the majority of these cells undergo apoptosis during the contraction phase, while the surviving cells differentiate into memory CD8+ T cells that serve as a critical component of long-term immunity. The pro-apoptotic Bcl-2 family member Bim is important for normal immune system homeostasis and contraction during shutdown of immune responses. Therefore, we have examined the role of Bim in the contraction of antigen-specific T cells following both acute and chronic LCMV infection. Following acute LCMV infection, we observed a transient delay in the contraction of antigen-specific CD8+ T cells in Bim-/- mice compared to wildtype, however contraction eventually ensues and the number of cells only remains slightly elevated compared to wildtype at later time points postinfection. However, the contraction of DbNP396-404+CD8+ T cells, the population that undergoes massive death in wildtype mice, was blocked in Bim-/- mice following LCMV Clone 13 infection, while DbGP33-41CD8+ and DbGP276-286CD8+ T cells underwent similar decreases in cell numbers in both Bim-/- and wildtype mice. When viral titers were examined, high titers were observed in the tissues of both Bim-/- and wildtype animals, but there was slightly accelerated clearance in the spleen and serum of Bim-/- mice. Since loss of Bim function did not result in a block in the contraction of all antigen-specific CD8+ T cell populations following both acute and chronic LCMV infection, we hypothesized that multiple mechanisms of apoptosis are used to down-regulate CD8+ T cell responses following viral infection. This led us to examine the additional effect of Fas, a Tumor Necrosis Factor Receptor (TNFR) superfamily member of the extrinsic pathway, on contraction following LCMV infection. We demonstrate that loss of both Bim and Fas function resulted in exacerbated autoimmunity compared to the parental genotypes and organ-specific blocks on contraction following antiviral immune responses. Bim-/-Faslpr/lpr mice contained significantly increased numbers of antigen-specific CD8+ T cells compared to the parental genotypes following acute LCMV infection. Although loss of both Bim and Fas function resulted in an increased number of antigen-specific CD8+ T cells in the lymph nodes, it was unclear whether blocking apoptosis rescued effector cells or if true memory CD8+ T cells were generated. In this study, we demonstrate that these are bona fide memory T cells as characterized by surface marker expression, cytokine production, homeostatic proliferation, and ability to clear a secondary challenge of pathogen. In contrast, chronic LCMV infection of Bim-/-Faslpr/lpr mice resulted in similar numbers of antigen-specific CD8+ T cells compared to the Bim-/- parental genotype. Thus, other genes in addition to Bim and Fas are contributing to apoptosis that occurs during the contraction phase following chronic LCMV infection. These results demonstrate that multiple death pathways function concurrently to prevent autoimmunity and downsize T cell responses. Additionally, these studies illustrate that decreasing apoptosis increases the number of memory T cells following acute viral infection and therefore could increase the efficacy of vaccines.
Cell death
CD8+ T cells
Lyles, Douglas (committee chair)
Grayson, Jason (committee member)
Alexander-Miller, Martha (committee member)
Schwartz, Elizabeth (committee member)
Parks, Griffith (committee member)
2009-05-12T16:23:55Z (accessioned)
2010-06-18T18:58:47Z (accessioned)
2009-05-12T16:23:55Z (available)
2010-06-18T18:58:47Z (available)
2009-05-12T16:23:55Z (issued)
Microbiology & Immunology (discipline)
http://hdl.handle.net/10339/14795 (uri)
en_US (iso)
Wake Forest University
Release the entire work for access only to the Wake Forest University system for one year from the date below. After one year, release the entire work for access worldwide. (accessRights)

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