C-C Chemokine Receptor 7 Limits the T Cell Receptor Repertoire of Thymocytes in the Thymus 4756

Abstract Description C-C Chemokine receptor 7 (CCR7) has been studied extensively for its role in directing trafficking of immune cells to the thymus and within lymphoid tissues. The downstream signaling events, following CCR7 activation are not as well studied. Using C57/BL6 mice we show that CCR7 limits not the level of IgG immunoglobulins generated during an adaptive immune response, without compromising antibody affinity. To determine if expression of CCR7 expression in the peripheral regulatory T cells limits the immune response, we generated CCR7f/f-CD4-Cre mice, which disrupt CCR7 expression during the selection of DP thymocytes. Levels of immunoglobulins in CCR7f/f-CD4-Cre mice were not elevated when compared to the CD4-Cre controls. Since CCR7 promotes migration to the thymus, we sequenced and compared the repertoires of the complementarity determining 3 regions (CDR3) of the CCR7-/-, CCR7f/f-CD4-Cre, and C57BL/6 mice. We found that CCR7 expression limits the CDR3 repertoire. To define the signaling events that are regulated by CCR7 we examined the effects of CCL19 vs. CCL21 on the kinetic proofreading events in T cells, that are thought to limit the TCR repertoire. We found that CCL21 but not CCL19 prolongs and enhances signaling via the TCR to phospholipase Cγ1. These data demonstrate for the first time a CCR7/CCL21 signaling pathway that is activated during thymocyte development that limits the repertoire of TCRs, to control the immune repertoire. Funding Sources NIH-SC1GM111172 NIH 2U54MD007592 NIH 5UL1GM118970 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)