Co-inhibition of PD-1 and CD73 breaks tolerance of autoreactive CD4+ T cells in vivo 2362

Abstract Description How the immune system distinguishes self from foreign antigens is incompletely understood. Particularly, it is not known why vaccination with self and foreign peptides induces weak and strong expansion of antigen-specific CD4+ T cells, respectively. By utilizing computational analysis of the entire mouse MHCII peptidome, we demonstrate that negative selection in the thymus affects the naïve and vaccinated repertoires of CD4+ T cells only partially. More CD4+ T cells that bind an MHC-II Apolipoprotein (ApoB) tetramer than CD4+ T cells specific for murine cytomegalovirus (MCMV) m25 in naïve (unimmunized and uninfected) C57BL/6J mice show high expression of the co-inhibitory molecules PD1 and CD73. Simultaneous inhibition of PD1 and CD73 rescued the defective vaccine-induced expansion of ApoB-reactive CD4+ T cells and aligned their transcriptomes with those of m25-specific CD4+ T cells. Thus, co-expression of PD1 and CD73 is an important mechanism of peripheral tolerance that limits expansion of autoreactive CD4+ T cells. Our findings help to understand immune-related adverse events of cancer immunotherapy and have implications for the development of tolerogenic vaccines. Funding Sources This work was supported by the German Research Foundation (NE 2574/1-1 to FSN), and the National Institutes of Health (R35 HL145241 to KL, AI139749 and AI101423 to CAB). Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)