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Mechanisms Regulating Survival of Effector and Memory CD8+ T Cells
Author Info
Kurtulus, Sema
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368026339
Abstract Details
Year and Degree
2013, PhD, University of Cincinnati, Medicine: Immunology.
Abstract
Naive T cells recruited to respond to an infection often undergo 15-20 rounds of cell division. After the infection is cleared, most of these T cells die, while others survive and become memory cells. Such memory T cells are critical for protection from reinfection and are the ultimate goal of most vaccine strategies. The underlying mechanism(s) of how some T cells perish, while others survive remains an unanswered question. In this dissertation, we aimed to understand the mechanisms that control contraction of CD8
+
T cell responses to Lymphocytic choriomeningitis virus (LCMV) infection of mice. As the pro-apoptotic Bcl-2 family member Bim is central to the apoptotic contraction of T cells after they reach the peak of the response, we were particularly focused on how some T cells avoid Bim-mediated death. The known heterogeneity of the effector CD8
+
T cell population helped us distinguish between cells with a long-lived phenotype and cells with a shorter-lived phenotype, the former cells being marked by high expression of CD127 and low expression of KLRG1, while the latter cells express low levels of CD127 and high levels of KLRG1. In chapter 5, we report that the levels of Bim and Bcl-2 are correlated in the different effector T cell subsets. Longer-lived T cells expressed higher levels of Bim and Bcl-2, while shorter-lived T cells expressed lower levels of Bim and Bcl-2. Further, we found that Bcl-2 is critical for survival of both shorter-lived and longer-lived effector T cell subsets and that Bcl-2 dictated the levels of Bim that effector CD8
+
T cells were able to tolerate and survive. In this manner, Bcl-2 is critical for the development and persistence of long-lived effector T cells into the memory compartment. In chapter 6, we found that the effects of Bim on the contraction are T cell intrinsic, because T cell-specific loss of Bim recapitulated data obtained in mice with a germline deletion of Bim. We also found that the effects of Bim on the contraction of T cell responses are temporally restricted. Eventually, the short-lived subset of effector T cells undergoes attrition even in Bim-deficient mice. This effect is likely controlled by IL-15 availability, because when IL-15 becomes limiting, a second death mechanism that is likely mediated by another Bcl-2 family member is engaged. In chapter 7, we explored the apoptotic mechanism(s) underlying the CD8
+
T cell effector to memory transition via an
in vitro
differentiation system. Similar to our
in vivo
data, we found that optimal
in vitro
driven T cell memory generation requires Bcl-2. However, we also found that some effector T cells survived even in the absence of Bcl-2. Such survival involved a modulation of mTOR activity as inhibition of mTOR activity enhanced the T cell effector to memory transition by Bcl-2-dependent and –independent mechanisms. Thus, our results indicate that limited availability of cytokines is a critical regulator of survival during the contraction of T cell responses. These findings have important implications for the design of vaccines and immunotherapies.
Committee
David Hildeman, Ph.D. (Committee Chair)
Claire Chougnet, Ph.D. (Committee Member)
Fred Finkelman, M.D. (Committee Member)
Michael Jordan, M.D. (Committee Member)
David Plas, Ph.D. (Committee Member)
Pages
342 p.
Subject Headings
Immunology
Keywords
CD8+ T cell
;
Bim
;
Bcl-2
;
effector T cell
;
memory T cell
;
apoptosis
;
Recommended Citations
Refworks
EndNote
RIS
Mendeley
Citations
Kurtulus, S. (2013).
Mechanisms Regulating Survival of Effector and Memory CD8+ T Cells
[Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368026339
APA Style (7th edition)
Kurtulus, Sema.
Mechanisms Regulating Survival of Effector and Memory CD8+ T Cells.
2013. University of Cincinnati, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368026339.
MLA Style (8th edition)
Kurtulus, Sema. "Mechanisms Regulating Survival of Effector and Memory CD8+ T Cells." Doctoral dissertation, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368026339
Chicago Manual of Style (17th edition)
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Document number:
ucin1368026339
Download Count:
763
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This open access ETD is published by University of Cincinnati and OhioLINK.