AUTHOR=Van Laethem François , Saba Ingrid , Lu Jinghua , Bhattacharya Abhisek , Tai Xuguang , Guinter Terry I. , Engelhardt Britta , Alag Amala , Rojano Mirelle , Ashe Jennifer M. , Hanada Ken-ichi , Yang James C. , Sun Peter D. , Singer Alfred TITLE=Novel MHC-Independent αβTCRs Specific for CD48, CD102, and CD155 Self-Proteins and Their Selection in the Thymus JOURNAL=Frontiers in Immunology VOLUME=11 YEAR=2020 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01216 DOI=10.3389/fimmu.2020.01216 ISSN=1664-3224 ABSTRACT=

MHC-independent αβTCRs (TCRs) recognize conformational epitopes on native self-proteins and arise in mice lacking both MHC and CD4/CD8 coreceptor proteins. Although naturally generated in the thymus, these TCRs resemble re-engineered therapeutic chimeric antigen receptor (CAR) T cells in their specificity for MHC-independent ligands. Here we identify naturally arising MHC-independent TCRs reactive to three native self-proteins (CD48, CD102, and CD155) involved in cell adhesion. We report that naturally arising MHC-independent TCRs require high affinity TCR-ligand engagements in the thymus to signal positive selection and that high affinity positive selection generates a peripheral TCR repertoire with limited diversity and increased self-reactivity. We conclude that the affinity of TCR-ligand engagements required to signal positive selection in the thymus inversely determines the diversity and self-tolerance of the mature TCR repertoire that is selected.