In the thymus, high-affinity, self-reactive thymocytes are eliminated from the pool of developing T cells, generating central tolerance. Here, we investigate how developing T cells measure self-antigen affinity. We show that very few CD4 or CD8 coreceptor molecules are coupled with the signal-initiating kinase, Lck. To initiate signaling, an antigen-engaged T cell receptor (TCR) scans multiple coreceptor molecules to find one that is coupled to Lck; this is the first and rate-limiting step in a kinetic proofreading chain of events that eventually leads to TCR triggering and negative selection. MHCII-restricted TCRs require a shorter antigen dwell time (0.2 s) to initiate negative selection compared to MHCI-restricted TCRs (0.9 s) because more CD4 coreceptors are Lck-loaded compared to CD8. We generated a model (Lck come&stay/signal duration) that accurately predicts the observed differences in antigen dwell-time thresholds used by MHCI- and MHCII-restricted thymocytes to initiate negative selection and generate self-tolerance.
Bibliographical noteFunding Information:
We thank U. Schneider for animal husbandry and E. Traunecker and T. Krebs for cell sorting. This study was funded by grants to E.P. (310030-149972/1 and Synergia [SNF], Sybilla [EU FP7], and TerraIncognita [ERC]), A.K.C. (1-P01-AI091580 [NIH]), E.S.H. (R01-DK095077 [NIH]), and A.K.S. (BB/H001085/1 [BBSRC]). D.K.C. is a Wellcome Trust Career Development Fellow. A.K.S. is a Wellcome Trust Senior Investigator.
© 2014 Elsevier Inc.