Self-Reactive T Cells Selected on Thymic Cortical Epithelium Are Polyclonal and Are Pathogenic In Vivo

Abstract

AbstractPositive selection of CD4+ T cells requires that the TCR of a developing thymocyte interact with self MHC class II molecules on thymic cortical epithelium. In contrast, clonal deletion is mediated by dendritic cells and medullary epithelium. We previously generated K14 mice expressing MHC class II only on thymic cortical epithelium. K14 CD4+ T cells were positively, but not negatively, selected and had significant in vitro autoreactivity. Here, we examine the function of these autoreactive CD4+ T cells in more detail. Analysis of a series of K14-derived T hybrids demonstrated that the autoreactive population of CD4+ T cells is phenotypically and functionally diverse. Purified K14 CD4+ T cells transferred into lethally irradiated wild-type B6 mice cause acute graft vs host disease with bone marrow failure. Further, these autoreactive CD4+ T cells cause hypergammaglobulinemia and the production of autoantibodies when transferred into unirradiated wild-type hosts. Thus, positive selection by normal thymic cortical epithelial cells, unopposed by negative selection, produces polyclonal CD4+ T cells that are pathologic.