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Molecular Mechanisms of CD8+ T Cell Subset Differentiation and Activation-induced Cell Death

Jimin Zhang
B.S., Sun Yat-sen University - 2004

Thesis Advisor: Yufang Shi, Ph.D.
Graduate Program in Microbiology & Molecular Genetics

RWJMS Research Tower, Room V-10

Wednesday, August 14, 2013
3:00 p.m.


Antigenic stimulation of lymphocytes results in activation of various types of adaptive immune responses, depending on factors such as antigen characteristics, genetic background of the host, and the tissue microenvironment. The resulting T cell subsets with distinct cytokine production profiles determine the outcomes of immune reactions. Different T cell subsets can be generated in vitro by altering their cytokine environment and in vivo by manipulating different components of the immune system. However, the mechanisms underlying differentiation and homeostasis of different T cell subsets still remain largely elusive.
Generally, CD4+ T cells T cells could be differentiated into Th1 and Th2 cells. Recent studies have shown that CD4+ T cells could also be differentiated into other subsets, such as Th9, Th17 and Treg cells, in which TGF is commonly applied in the cytokine milieu, albeit different additional cytokines. Like the CD4+ T cell subsets, CD8+ T cells can also be differentiated into different subsets under certain pathophysiological conditions, with cytokine profiles resembling their CD4+ helper T cell counterparts. Unlike CD4+ T cell subsets, CD8+ T cell subsets have received much less attention.
In this study, I investigated the role of TGF in achieving the differentiation of the CD8+ counterparts: Tc9, Tc17 and CD8+ Treg cells, in addition to Tc1 and Tc2 cells. I showed that TGF inhibited expression of STAT4 and GATA-3 during the differentiation of Tc9, Tc17 and CD8+ Treg cells. Interestingly, I found that TGF is dispensable for the molecular orchestration of Tc17 cell differentiation, but is necessary for CD8+ Treg cell differentiation. Using T-bet and STAT6 double knockout mice, in which Tc1 and Tc2 cells were abolished, I demonstrated that IL-6 alone is sufficient to differentiate Tc17 cells. Moreover, I found that IL-4 and TGF driven Tc9 differentiation required STAT6. These results indicate that TGF indirectly promotes Tc17 differentiation by inhibiting the expression of key Tc1 and Tc2 differentiation factor, STAT4 and GATA-3. Similar mechanism may also operate during Tc9 differentiation.
Upon activation, excessive T cells of different subsets have to be removed in order to prevent harmful effects of overreacting immune responses. Activation-induced cell death (AICD) is a key mechanism for the maintenance of T cell homeostasis. However, it is not fully understood whether different T cell subsets employ the same AICD mechanism. Our previous studies have shown that Th1 cells undergo FasL-mediated AICD, while Th2 cells use granzyme B. I demonstrate here that, while AICD in Tc1 and Tc17 cells is FasL-mediated, Tc2 cells solely depend on TRAIL. TRAIL knockout or addition of soluble TRAIL receptors abolished AICD only in Tc2 cells, but not in Tc1 or Tc17 subsets. Interestingly, this TRAIL-mediated Tc2 cell death requires Bim translocation to mitochondria. Expectedly, Bim knockout prevented activation of effector caspases and subsequent AICD in Tc2, but not Tc1 cells. Significantly, TRAIL blockade aggravated airway inflammation mediated by OVA-specific TCR-transgenic Tc2 cells. These results revealed a novel mechanism controlling immune responses.
My studies provide critical information about how CD8+ T subsets are differentiated and how they undergo AICD. I believe that this information may aid in understanding immune responses during various pathophysiological conditions and the development of novel strategies for vaccine and immune therapies.

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