The role of CCR4 and CCR7 in the establishment of central tolerance
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T cells mediate adaptive immune responses against foreign pathogens, such as viruses and bacteria, or malignant cells. T cells rely on T cell receptors to recognize foreign or tumor antigens presented on MHC-I or MHC-II complexes. Upon antigen recognition, T cells are activated and carry out effector functions to eliminate the antigen bearing cells. Aberrant recognition of self-antigen, however, will cause damage to healthy tissue, leading to autoimmune diseases. To establish tolerance towards self-antigens, developing T cells in the thymus (thymocytes) undergo stringent selection processes. During their final stages of maturation, thymocytes are exposed to a wide range of self-antigens presented by antigen presenting cells (APCs), such as dendritic cells and medullary thymic epithelium cells, in the medullary region of the thymus. Auto-reactive thymocytes that recognize self-antigens either undergo apoptosis or are diverted into the regulatory T cell lineage. Regulatory T cells (Treg) directly suppress effector functions of autoreactive T cells. Thus, both deletion and diversion into the Treg lineage are critical for averting autoimmunity. The cellular and molecular mechanisms governing thymocyte tolerance induction are incompletely understood. In this dissertation, I describe previously unreported roles for the chemokine receptors CCR4 and CCR7 in the establishment of tolerance in thymus. In order for thymocytes to encounter the full range of antigens against which they could be autoreactive, they must undergo efficient interactions with APCs in the medulla. However, the mechanisms promoting thymocyte medullary entry and interactions with APCs therein are not well understood. In chapter 2, I demonstrate that CCR4 is required for medullary entry of the earliest subset of thymocytes that enters the medulla and promotes their interactions with dendritic cells, one of the two major APC types in the thymic medulla. In keeping with the importance of these two activities for the induction of self-tolerance, in the absence of CCR4, autoreactive T cells are not efficiently eliminated and autoimmunity ensues. Regulatory T cells suppress immune responses initiated by auto-reactive T cells that escaped from thymus, and are therefore essential for maintaining self-tolerance. The regulation of regulatory T cell differentiation in the thymus is not fully understood. In chapter 3, I identify a novel role for CCR7 in controlling thymic regulatory T cell generation. Interestingly, CCR7 does not contribute to regulatory T cell induction due to its expression by thymocytes; instead, CCR7 expression on DCs modulates regulatory T cell generation by altering the composition of the thymic DC compartment. I found that CCR7 promotes survival of Sirpα- dendritic cells, one of the two major subsets of dendritic cells in the thymus. In the absence of CCR7, Sirpα- dendritic cells are preferentially lost, enabling an increase in the relative abundance of Sirpα+ dendritic cells, which more efficiently promote regulatory T cell generation. As a result, regulatory T cell generation is increased in CCR7-deficient mice, especially at the early neonatal stage, when regulatory T cell induction is particularly critical for the establishment of self-tolerance. The novel functions of CCR4 and CCR7 discovered by our studies provide new insights into the cellular and molecular mechanisms that govern T cell tolerance induction and will provide rationale for development of new therapies for autoimmune disorders.