Immune responses must be regulated to ensure effective pathogen elimination and self tolerance. ICOS and PD-L1 play key roles in regulating this critical balance between T cell activation and tolerance. During the current funding period, we have been investigating how ICOS and PD-L1 in regulate pathogenic vs. protective T cell responses. Our studies point to novel roles for both ICOS and PD-L1 In sustaining the function of regulatory T cell cells and maintaining T cell tolerance. We have found that ICOS does not control the induction of regulatory CD4 T cells during mucosal tolerance, but instead, appears necessary for sustaining CD4 regulatory cells during mucosal tolerance. ICOS, c-Maf and IL-21 coordinately act to promote differentiation of IL-10 producing regulatory type 1 (Tr1) cells, but ICOS appears to be crucial for maintaining IL-27 driven, IL-10 producing Tri cells. These findings lead us to hypothesize that ICOS, c-maf and lL-27 wori These studies will provide new insights into how ICOS and PD-L1 regulate the balance between T cell activation and tolerance. The results of our studies will have implications for developing new therapies for human chronic viral infections, cancer, autoimmune diseases and increasing success of transplantation. Our findings may assist with approaches for controlling Treg plasticity and help determine how to tiest manipulate PD-L1 therapeutically to enhance pathogen or tumor control, and minimize autoimmunity/immunopathology.Public Health Relevance
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