Project Grant R21AI185642

T CELL-MEDIATED CONTROL OF DERMAL FIBROBLAST GENE PROGRAMS AND DYSFUNCTION IN SCLERODERMA - PROJECT SUMMARY/ABSTRACT SYSTEMIC SCLEROSIS (SSC), ALSO KNOWN AS SCLERODERMA, IS AN IDIOPATHIC DISEASE OF THE CONNECTIVE TISSUE CHARACTERIZED BY FIBROSIS OF THE SKIN AND UNDERLYING ORGANS. IT HAS THE HIGHEST MORTALITY OF ALL RHEUMATIC CONDITIONS AND NO CURE. T CELLS PREDOMINATE IN LESIONAL SSC SKIN AND PATIENT SERUM IS ENRICHED IN T CELL CYTOKINES. IMMUNOSUPPRESSION THAT LIMITS T CELL FUNCTION CAN DECREASE SYMPTOMS OF FIBROSIS, BUT ALSO INCREASES PATIENT SUSCEPTIBILITY TO INFECTION. AN ARRAY OF FUNCTIONALLY DISTINCT T CELLS ARE IN CLOSE-CONTACT WITH FIBROBLASTS IN HEALTHY SKIN, AND DYSREGULATED T CELL-FIBROBLAST CROSSTALK IS THOUGHT TO BE A MAJOR DRIVER OF DISEASE PATHOLOGY. HOWEVER, WHILE T CELLS ARE IMPLICATED IN SSC PROGRESSION, NO STUDIES HAVE PERFORMED A RIGOROUS MECHANISTIC DISSECTION OF T CELL-DIRECTED CHANGES TO FIBROBLAST GENE PROGRAMS IN HEALTHY AND FIBROTIC SKIN. WE PREVIOUSLY IDENTIFIED A NOVEL POPULATION OF CUTANEOUS CD4+CLA+CD103+ T CELLS IN THE BLOOD AND SKIN THAT CO-PRODUCE IL-22 AND IL-13 IMPLICATING A ROLE IN SKIN HOMEOSTASIS. WE NOW FIND THAT THE FREQUENCY OF THESE AND OTHER CUTANEOUS T CELLS ARE ALTERED IN SSC, THOUGH THEIR FUNCTION IN AFFECTED PATIENT SKIN REMAINS UNEXPLORED. OUR NOVEL PRELIMINARY DATA SHOW THAT DIFFERENT CUTANEOUS T CELL POPULATIONS PROMOTE DISTINCT FIBROBLAST GENE SIGNATURES AND DEMONSTRATE A STRONG CD103+ T CELL-DEPENDENT EFFECT ON A NEWLY IDENTIFIED SSC-ASSOCIATED FIBROBLAST SUBSET. WE THEREFORE HYPOTHESIZE THAT CD103+ T CELL ACTIVITY IS ESSENTIAL FOR FIBROBLAST HOMEOSTASIS AT THE STEADY STATE AND THAT NORMAL T CELL-FIBROBLAST INTERACTIONS ARE DISRUPTED IN SSC, LEADING TO FIBROBLAST DYSFUNCTION. THIS PROPOSAL WILL USE SINGLE- CELL SPATIAL TRANSCRIPTOMICS AND INNOVATIVE ORGANOTYPIC SKIN CULTURE TO FILL CRITICAL KNOWLEDGE GAPS AND OVERCOME EXISTING TECHNICAL HURDLES IN THE FIELD. COMPLETION OF THESE AIMS WILL BUILD A FOUNDATION FOR THE GENERATION OF EXCITING NEW HYPOTHESIS AND WILL ADVANCE A NOVEL ORGANOTYPIC CULTURE MODEL WITH THE POTENTIAL TO RECAPITULATE IN VIVO FIBROBLAST HETEROGENEITY ASSOCIATED WITH DISEASE AND TISSUE DYSFUNCTION.