Force-regulated in situ TCR-peptide-bound MHC class II kinetics determine functions of CD4+ T cells

Jinsung Hong, Stephen P. Persaud, Stephen Horvath, Paul M. Allen, Brian D. Evavold, Cheng Zhu

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

We have recently shown that two-dimensional (2D) and force-regulated kinetics of TCR-peptide-bound MHC class I (pMHC-I) interactions predict responses of CD8+ T cells. To test whether these findings are applicable to CD4+ T cells, we analyzed the in situ 3.L2 TCR-pMHC-II interactions for a well-characterized panel of altered peptide ligands on the T cell surface using the adhesion frequency assay with a micropipette and the thermal fluctuation and force-clamp assays with a biomembrane force probe. We found that the 2D effective TCR-pMHC-II affinity and off-rate correlate with, but better predict the T cell response than, the corresponding measurements with the surface plasmon resonance in three dimensions. The 2D affinity of the CD4 for MHC-II was very low, approaching the detection limit, making it one to two orders of magnitude lower than the affinity of CD8 for MHC-I. In addition, the signal-dependent cooperation between TCR and coreceptor for pMHC binding previously observed for CD8 was not observed for CD4. Interestingly, force elicited TCR-pMHC-II catch-slip bonds for agonists but slip-only bonds for antagonists, thereby amplifying the power of discrimination between altered peptide ligands. These results show that the force-regulated 2D binding kinetics of the 3.L2 TCR for pMHC-II determine functions of CD4+ T cells.

Original languageEnglish
Pages (from-to)3557-3564
Number of pages8
JournalJournal of Immunology
Volume195
Issue number8
DOIs
StatePublished - Oct 15 2015

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