A TCR mechanotransduction signaling loop induces negative selection in the thymus
The T cell antigen receptor (TCR) expressed on thymocytes interacts with self-peptide major histocompatibility complex (pMHC) ligands to signal apoptosis or survival. Here, we found that negative-selection ligands induced thymocytes to exert forces on the TCR and the co-receptor CD8 and formed cooperative TCR–pMHC–CD8 trimolecular ‘catch bonds’, whereas positive-selection ligands induced less sustained thymocyte forces on TCR and CD8 and formed shorter-lived, independent TCR–pMHC and pMHC–CD8 bimolecular ‘slip bonds’. Catch bonds were not intrinsic to either the TCR–pMHC or the pMHC–CD8 arm of the trans (cross-junctional) heterodimer but resulted from coupling of the extracellular pMHC–CD8 interaction to the intracellular interaction of CD8 with TCR–CD3 via associated kinases to form a cis (lateral) heterodimer capable of inside-out signaling. We suggest that the coupled trans–cis heterodimeric interactions form a mechanotransduction loop that reinforces negative-selection signaling that is distinct from positive-selection signaling in the thymus.
Hong, J., Ge, C., Jothikumar, P., Yuan, Z., Liu, B., Bai, K., Li, K., Rittase, W., Shinzawa, M., Zhang, Y., Palin, A., Love, P., Yu, X., Salaita, K., Evavold, B., Singer, A., & Zhu, C. (2018). A TCR mechanotransduction signaling loop induces negative selection in the thymus. Nature Immunology, 19 (12), 1379-1390. https://doi.org/10.1038/s41590-018-0259-z