PD-1 and CD73 synergistically limit CD4 T cell responses to autoantigens

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Presentation Time: 02:15 PM - 03:30 PM
Poster Board Number: B224
Abstract ID: 6106

Presenting Author:
Felix S Nettersheim , postdoc at La Jolla Inst. for Immunol.

Abstract:

One of the central tenets of immunology is that the adaptive immune system distinguishes self from non-self. It has been proposed that the naïve CD4 T cell repertoire specific for a given autoantigen is shaped by negative selection in the thymus. Herein, we demonstrate that vaccination against self-epitopes induces a considerably smaller expansion of CD4 T cells compared to a vaccination against foreign epitopes, although the naïve repertoire of CD4 T cells reactive to self and foreign epitopes was similar. We used computational analysis of the MHC-II binding mouse peptidome, MHC-II tetramers, single cell and bulk RNA sequencing, and pharmacological interventions to identify the mechanism that limits clonal expansion of CD4 T cells upon vaccination with self epitopes. We found that the number of self peptide epitopes does not explain the weak vaccine-response to self. scRNA-Seq showed higher PD1 and CD73 expression in self- (ApoB p6) vs. foreign-reactive (MCMV m25) CD4 T cells in naïve (unvaccinated and uninfected) mice. Co-inhibition of PD1 and CD73 induced a substantial increase in the CD4 T cell response to ApoB p6 vaccination, inducing expansion similar to that seen with MCMV m25 vaccination. PD1 and CD73 co-inhibition moved the transcriptomes of tetramer-sorted ApoB p6 T cells close to the transcriptomes of T cells specific for MCMV m25. We conclude that PD-1 and CD73 are the key CD4 T cell surface molecules limiting expansion of CD4 T cells upon vaccination to self.