Title

Cellular and molecular mechanisms underlying naive and effector CD4 cell tolerization

Date of Completion

January 2007

Keywords

Biology, Cell|Health Sciences, Immunology

Degree

Ph.D.

Abstract

The induction of antigen-specific T cell tolerance in the periphery is essential to prevent autoimmune diseases and also helps tumors to evade immune neutralization. Dissecting the mechansims that mediate peripheral T cell tolerance will therefore aid in the development of therapeutic strategies to manage these diseases. ^ Previous data from our lab and other groups has shown that not only naïve, but also effector/memory T cells that are initially primed by viral antigens can undergo peripheral tolerization in response to self-antigen. This thesis describes cellular and molecular mechanisms that regulate the tolerization of both naïve and Th1 effector CD4 cells. Interestingly, during the tolerization of Th1 effectors, functions such as the ability to produce the effector cytokines IFN-γ and TNF-α are lost more rapidly than non-effector functions such as the ability to proliferate and to produce IL-2. These functional loses are conferred primarily through the development of cell-intrinsic signaling defects that are located relative to the T cell receptor (TCR) both proximally (which impair the expression of all cytokines) and distally (which selectively impairs the expression of IFN-γ and TNF-α). Furthermore, the down-modulation of T-bet, a key transcription factor that directs the differentiation of naïve CD4 cells into IFN-γ-expressing Th1 effectors, was identified as a TCR-distal defect that selectively impairs IFN-γ, but not TNF-α, expression. Although T-bet controls IFN-γ expression in part through programming remodeling of the IFN-γ gene locus from an closed/repressed to open/transcriptionally competent configuration, analysis of histone acetylation at the IFN-γ promoter indicated that down-modulation of T-bet expression during Th1 effector CD4 cell tolerization does not impair IFN-γ expression potential through alterations in chromatin structure. ^ Although naïve CD4 cells undergoing tolerization only develop weak capacity to express IFN-γ, we made the surprising finding that the IFN-γ gene locus nevertheless undergoes remodeling, and that the inability to express IFN-γ in response to antigenic stimulation is primarily due to the development of a TCR-proximal signaling defect. Interestingly, it appears that IL-2 (a cytokine whose absence is generally associated with tolerance) produced by naïve CD4 cells undergoing tolerization actually drives the remodeling of the IFN-γ gene. During these studies we also made the surprising finding that in naïve CD4 cells undergoing both virally-induced Th1 differentiation and self-antigen-induced tolerization that IL-2 expression and IL-2 signaling (as measured by STAT5 activation) were largely mutually-exclusive. Thus, paracrine, rather than autocrine, IL-2 signaling appears to be the dominant signaling mode during early CD4 cell response. ^

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