Tu129 - Human T Cell Behavior in Lymphopenic Environments: Contribution of Lymphopenia-induced Proliferation to Autoimmunity

Haowei Li – Columbia Center for Translational Immunology – Columbia University; Farshid Fathi – Columbia Center for Translational Immunology – Columbia University; Nathan Suek – Columbia Center for Translational Immunology – Columbia University; Markus Hoelzl – Columbia Center for Translational Immunology – Columbia University; Aditya Misra – Columbia Center for Translational Immunology – Columbia University; Samantha Gaines; Robert Winchester – Columbia Center for Translational Immunology – Columbia University; Megan Sykes – Columbia Center for Translational Immunology – Columbia University

Abstract Text: Considerable evidence suggests a role for lymphopenia-induced proliferation (LIP) of T cells in the initiation or facilitation of autoimmunity in both mice and humans. TCR interactions with p.MHC are central to the development of autoimmunity. However, the relative contribution of cytokines vs antigen recognition to the LIP that promotes autoimmunity and the role of LIP in human autoimmunity is poorly understood. Using adoptive transfer of T cells in human immune system (HIS) mice, we now demonstrate that both naïve and memory human T cells undergo rapid proliferation in T cell-deficient HIS mice and promote the development of autoimmune disease. We demonstrate that T cells recognizing p.HLA of selecting thymic epithelium undergo faster LIP and induce faster autoimmunity upon adoptive transfer. In the absence of interactions with p.HLA:TCR present in the thymus, IL-7 does not induce T cell survival and proliferation. Interaction of T cells undergoing LIP with myeloid cells presenting the p.HLA that the T cells were selected on led to maturation of the myeloid cells. TCR sequencing confirmed the clonal expansion of T cells with increased hydrophobicity of amino acids at their CDR3Bs predictive of high peptide recognition. Through the adoptive transfer of different T cell subsets, we established that non-Treg CD4 T cells were mainly responsible for the observed autoimmune disease. These studies shed light on mechanisms of T cell activation and proliferation in lymphopenic environments and LIP-induced autoimmunity.