Immune responses must be regulated to ensure effective pathogen elimination and self tolerance. ICOS andPD-L1 play key roles in regulating this critical balance between T cell activation and tolerance. During thecurrent 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 thefunction of regulatory T cell cells and maintaining T cell tolerance. We have found that ICOS does not controlthe induction of regulatory CD4 T cells during mucosal tolerance, but instead, appears necessary forsustaining CD4 regulatory cells during mucosal tolerance. ICOS, c-Maf and IL-21 coordinately act topromote differentiation of IL-10 producing regulatory type 1 (Tr1) cells, but ICOS appears to be crucial formaintaining IL-27 driven, IL-10 producing Tri cells. These findings lead us to hypothesize that ICOS, c-mafand lL-27 wori< in concert to regulate mucosal tolerance. Likewise, we have identified mechanisms by whichPD-L1 controls tolerance: PD-L1 limits activation of self-reactive T cells, function of self-reactive effector cellsand promotes induction and maintenance of adaptive regulatory T cells. PD-L1 on non-hematopoietic cellspromotes tissue tolerance. PD-L1 and PD-1 have become new therapeutic targets in cancer and chronicinfection, since blockade of PD-1 or PD-L1 can activate anti-viral or anti tumor immunity. In view of their keyroles In regulating tolerance, further studies are needed to determine how to effectively minimize the risk ofimmune-mediated tissue damage and autoimmunity, while modulating PD-L1 and PD-1 to enhance virus ortumor control. Our discovery of the PD-L1 :B7-1 pathway leads us to ask whether PD-L1 :PD-1 and PD-L1:B7-1 interactions have unique or overiapping roles in T cell tolerance, and investigate the function of PD-L1 on T cells during tolerance. We hypothesize that PD-L1:B7-1, as well as PD-L1:PD-1 interactions, inhibitself-reactive T cell responses, and that PD-L1 has a T cell intrinsic role in controlling T cell responses. Totest these hypotheses, our Specific Aims are to: 1) Investigate the inter-relationships among ICOS, IL-27 andc-maf during mucosal tolerance; 2) Analyze the functional significance of the novel PD-L1:B7-1 pathway andrelative contributions of PD-L1:B7-1 and PD-L1 interactions in regulating T cell tolerance and autoimmunity;3) Investigate the role of PD-L 1 onT cells in regulating T cell tolerance; and 4) Dissect the roles of PD-L 1 onspecific cell types in mucosal tolerance. These studies should complement each other to further ourunderstanding of mechanisms that control tolerance and autoimmunity, and provide therapeutic insights.
These studies will provide new insights into how ICOS and PD-L1 regulate the balance between T cellactivation and tolerance. The results of our studies will have implications for developing new therapies forhuman chronic viral infections, cancer, autoimmune diseases and increasing success of transplantation. Ourfindings may assist with approaches for controlling Treg plasticity and help determine how to tiest manipulatePD-L1 therapeutically to enhance pathogen or tumor control, and minimize autoimmunity/immunopathology.
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