Exploiting the Mechanobiology of PD-1 for Cancer Immunotherapy

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Project Summary Alopecia Areata (AA) is an autoimmune disease affecting ~2% of the world population, especially affecting black women disproportionately, with no cure at the present time. It manifests as inflammatory response of the hair follicles where immune cells, cytotoxic T cells in particular, attack self-tissue, resulting in hair loss. The mechanism underlying this autoimmune reaction is incomplete understood, and the disease-driving antigens recognized by the specific T-cell receptors (TCR) are not known. The objectives of this project are to identify and characterize Alopecia Areata-specific and force sensitive antigen and cognate TCRs. It is widely accepted that the disease is induced by a loss of immune privilege in hair follicles, leading to the loss of immune tolerance of a subpopulation of CD8+ T cells that recognize self-antigens. We hypothesize that the self-antigen peptide-histocompatibility complex (pMHC) interaction with TCR is stronger than those that provide tonic signals for T cell survival but weaker than the pathogenic-pMHC-TCR interactions. The two specific aims are: 1) To identify AA-driving antigens and their cognate TCRs in human and mouse using a newly developed pMHC-tetramer library-stained single-cell sequencing technique. 2) To characterize the force-dependent AA-pMHC-TCR interaction and compare it with self- and pathogenic- pMHC-TCR interactions using the biomembrane force probe technology of the Zhu lab. Completing these aims will pave the way for future studies investigating TCR signaling induced by pMHC, the resulting T-cell activation/function, improved transgenic TCR mouse models for AA, and an eventual cure.