Project Grant R01DK140741

FROM GUT TO BLOOD: DISSECTING THE MECHANISMS OF CD4+ T CELL PATHOLOGY IN ISLET AUTOIMMUNITY ACROSS TISSUE ENVIRONMENTS. - ENTER THE TEXT HERE THAT IS THE NEW ABSTRACT INFORMATION FOR YOUR APPLICATION. THIS SECTION MUST BE NO LONGER THAN 30 LINES OF TEXT. TYPE 1 DIABETES (T1D) IS AN AUTOIMMUNE DISEASE TRIGGERED BY GENETICS AND ENVIRONMENTAL FACTORS. IN PARTICULAR, THE GUT MICROBIOTA HAS BEEN IMPLICATED IN T1D PATHOGENESIS. BACTERIAL COLONIZATION MODIFIES ISLET AUTOIMMUNITY IN MICE. CHANGES IN MICROBIAL COMPOSITION AND DIVERSITY HAVE ALSO BEEN REPORTED IN CHILDREN WHO DEVELOPED T1D. MICROBES HAVE BEEN PROPOSED TO DRIVE AUTOIMMUNITY VIA MOLECULAR MIMICRY, WHERE MICROBIAL EXPOSURE TRIGGERS AN INAPPROPRIATE RESPONSE FROM SELF-REACTIVE T CELLS RECOGNIZING A SIMILAR APPEARING MICROBIAL ANTIGEN. HOWEVER, AUTOREACTIVE T CELLS AND CROSS-REACTIVE RECOGNITION ARE NOT LIMITED TO DISEASE; THEY ARE ALSO PRESENT IN A HEALTHY IMMUNE REPERTOIRE. HOW AUTOIMMUNE PATHOLOGY ARISES FROM THESE PHYSIOLOGIC INTERACTIONS REMAINS UNKNOWN. IN COLLABORATION WITH THE NIDDK HUMAN PANCREAS ANALYSIS PROGRAM (HPAP) AT THE UNIVERSITY OF PENNSYLVANIA, WE EXAMINED CD4+ T CELLS ISOLATED FROM THE DUODENUM AND PANCREATIC ISLETS OF RECENT ONSET T1D AND HEALTHY ORGAN TRANSPLANT DONORS. CD4+ LAMINA PROPRIA LYMPHOCYTES (LPL) IN T1D PATIENTS, INCLUDING THOSE RECOGNIZING COMMENSAL BACTERIA, EXHIBITED ALTERED RESPONSES TO STIMULATION. CONCURRENT TCR SEQUENCE ANALYSES ON COMMENSAL-REACTIVE T CELLS FURTHER SHOWED A BROADER PATTERN OF ANTIGEN-RECOGNITION IN T1D PATIENTS. BASED ON THESE FINDINGS, WE HYPOTHESIZE THAT T CELLS IN AUTOIMMUNE PATIENTS ARE MORE CROSS-REACTIVE, POTENTIALLY ENABLING INAPPROPRIATE COMMENSAL RESPONSES TO TARGET SELF-ANTIGENS. BECAUSE T1D-ASSOCIATED GENE SIGNATURES CAN BE DETECTED BEFORE CLINICAL DIAGNOSIS AND ARE PRESENT IN CIRCULATING T CELLS, WE FURTHER PROPOSE THAT TISSUE PATHOLOGY CAN BE DETECTED IN PERIPHERAL BLOOD TO OFFER NEW OPPORTUNITIES FOR EARLY DETECTION AND INTERVENTION. IN AIM 1, WE WILL DEFINE CROSS-REACTIVITY BETWEEN MICROBIAL AND SELF-ANTIGENS AND TEST THE HYPOTHESIS THAT T1D AND AT-RISK INDIVIDUALS HAVE A BROADER BREADTH OF T CELL RECOGNITION. IN AIM 2, WE WILL BUILD ON OUR FINDINGS IN THE LPL TO IDENTIFY KEY PROPERTIES OF GUT-ASSOCIATED T CELL RESPONSES IN THE BLOOD. OUR GOAL IS TO IDENTIFY NOVEL CELLULAR BIOMARKERS FOR T1D. PBMCS FROM TRIALNET, COLLECTED AT VARIOUS STAGES OF ISLET AUTOIMMUNITY BEFORE DISEASE ONSET, WILL BE USED TO IDENTIFY KEY IMMUNE SIGNATURES THAT CAN PREDICT DISEASE ONSET AND PROGRESSION. DATA GENERATED FROM THIS STUDY WILL PROVIDE FUNDAMENTAL KNOWLEDGE ON THE UNDERLYING IMMUNE PATHOLOGY IN T1D AND MAY UNCOVER NEW BIOMARKERS FOR ISLET AUTOIMMUNITY. THE PROPOSED RESEARCH WILL THEREFORE HAVE A BROAD IMPACT ON T1D RESEARCH.