The role of IL-2Rbeta-dependent signaling and CD103 in regulatory T cells for mucosal tolerance

摘要: of a dissertation at the University Miami. Dissertation supervised by Professor Thomas R. Malek. No. pages in text. (124) A network mechanisms operates to maintain tolerance gut mucosa. CD103 marks many lymphoid cells, including regulatory T cells (Tregs), within gut. Tregs represent subset with potent suppressor function vitro and vivo. However, other features this remain undefined. In current study, we found that Treg exhibited more activated phenotype showed increased suppressive activity preventing inflammation small intestine. We also low IL-2R signaling had localized effect on peripheral organ vs. tissue site. With respect intestinal tolerance, may be part redundant pathway as mice do not exhibit autoimmunity. To reduce such redundancy, were crossed (designated Y3) whose expressed mutant IL-2Rβ chains lower signaling. Unlike Y3 only symptoms mild autoimmune attack, all Y3/CD103 rapidly developed severe colitis. The large intestine these contained an increase CD4 helper (Th)1 Th17 effector reduced ratio Tregs. Importantly, colitis was effectively prevented transfer wild type (WT) into mice. Impaired attributed obvious lack CD103-dependent gene regulation or homing/retention nor functional activities typically associated dendritic (DCs), induced (pTreg) development imprinting CCR9 α4β7 homing molecules cells. Transcriptome analysis consistent altered homeostasis due impaired IL-2Rβ-dependent minimal dysregulation added absence CD103. Rather functioned further dysregulate through mechanism primarily improper localization microenvironment prevent receiving optimal survival signals. Thus, normally cooperate distinctive processes promote immune tolerance.