MECHANISITIC STUDIES OF TISSUE-RESIDENT T CELL MATURATION IN THE KIDNEY

After successful clearance of an infection, a significant number of memory T cells remain in both lymphoid andnon-lymphoid tissues to protect against re-infection. Tissue-resident memory T (TRM) cells are a population ofmemory T cells localized to non-lymphoid tissues without continuous re-circulation. In adult human andimmunized mice, there are large number of TRM cells localized to a variety of organs that are often targets ofautoimmune and/or inflammatory disorders, such as the kidney, liver, brain, skin and gastrointestinal tract.However, the connection between TRM cells and autoimmune/ inflammatory disorders remains largely elusive.Whether and how TRM cells are involved in autoimmune and/or inflammatory diseases are unclear. Circulatingmemory T cells respond to both antigen-specific and antigen-non-specific stimuli. It is well established thatnon-specific inflammation induce rapid and NK cell-like responses from circulating memory CD8+ T cells toprovide immediate protection against bystander infections. Cognate antigen induces robust response of TRMcells. How TRM cells respond to antigen-non-specific bystander inflammation remains unknown. Consideringthat most TRM cells reside in vital tissues, antigen-non-specific response of TRM cells may lead to unwantedtissue damage and initiate or accelerate autoimmune or inflammatory disorders.Our preliminary findings have demonstrated that after viral infection, the responsiveness to bystanderinflammation is specifically decreased during TRM cell maturation. This step of TRM cell maturation is dependenton transforming growth factor-? (TGF-?) signaling to TRM cells. However, the transcription networksdownstream of TGF-? signaling remain unknown. We have identified five transcription factors that aredynamically regulated in a TGF-?-dependent manner during TRM maturation. In the current proposal, we willdetermine the role of these five candidate transcription factors during TRM cell maturation. Further, using bothgain-of-function and loss-of-function approaches, we will determine whether disrupted TRM cell maturationleads to unwanted collateral tissue damage during un-related bystander infection.Together, we propose to investigate the mechanistic control of a novel maturation step during TRMdifferentiation following acute infection. Further, we will elucidate the functional consequence of defective TRMmaturation during bystander infection-induced tissue damage. We will provide evidence that TRM cells are acritical link between infection and autoimmune/inflammatory disorders.Project SummaryAfter successful clearance of an infection, a significant number of memory T cells remain in both lymphoid andnon-lymphoid tissues to protect against re-infection. Tissue-resident memory T (TRM) cells are a population ofmemory T cells localized to non-lymphoid tissues without continuous re-circulation. In adult human andimmunized mice, there are large number of TRM cells localized to a variety of organs that are often targets ofautoimmune and/or inflammatory disorders, such as the kidney, liver, brain, skin and gastrointestinal tract.However, the connection between TRM cells and autoimmune/ inflammatory disorders remains largely elusive.Whether and how TRM cells are involved in autoimmune and/or inflammatory diseases are unclear. Circulatingmemory T cells respond to both antigen-specific and antigen-non-specific stimuli. It is well established thatnon-specific inflammation induce rapid and NK cell-like responses from circulating memory CD8+ T cells toprovide immediate protection against bystander infections. Cognate antigen induces robust response of TRMcells. How TRM cells respond to antigen-non-specific bystander inflammation remains unknown. Consideringthat most TRM cells reside in vital tissues, antigen-non-specific response of TRM cells may lead to unwantedtissue damage and initiate or accelerate autoimmune or inflammatory disorders.Our preliminary findings have demonstrated that after viral infection, the responsiveness to bystanderinflammation is specifically decreased during TRM cell maturation. This step of TRM cell maturation is dependenton transforming growth factor-? (TGF-?) signaling to TRM cells. However, the transcription networksdownstream of TGF-? signaling remain unknown. We have identified five transcription factors that aredynamically regulated in a TGF-?-dependent manner during TRM maturation. In the current proposal, we willdetermine the role of these five candidate transcription factors during TRM cell maturation. Further, using bothgain-of-function and loss-of-function approaches, we will determine whether disrupted TRM cell maturationleads to unwanted collateral tissue damage during un-related bystander infection.Together, we propose to investigate the mechanistic control of a novel maturation step during TRMdifferentiation following acute infection. Further, we will elucidate the functional consequence of defective TRMmaturation during bystander infection-induced tissue damage. We will provide evidence that TRM cells are acritical link between infection and autoimmune/inflammatory disorders.