Abstract
T cells use the αβ T cell receptor (TCR) to recognize antigenic peptides presented by class I major histocompatibility complex proteins (pMHCs) on the surfaces of antigen-presenting cells. Flexibility in both TCRs and peptides plays an important role in antigen recognition and discrimination. Less clear is the role of flexibility in the MHC protein; although recent observations have indicated that mobility in the MHC can impact TCR recognition in a peptide-dependent fashion, the extent of this behavior is unknown. Here, using hydrogen/deuterium exchange, fluorescence anisotropy, and structural analyses, we show that the flexibility of the peptide binding groove of the class I MHC protein HLA-A*0201 varies significantly with different peptides. The variations extend throughout the binding groove, impacting regions contacted by TCRs as well as other activating and inhibitory receptors of the immune system. Our results are consistent with statistical mechanical models of protein structure and dynamics, in which the binding of different peptides alters the populations and exchange kinetics of substates in the MHC conformational ensemble. Altered MHC flexibility will influence receptor engagement, impacting conformational adaptations, entropic penalties associated with receptor recognition, and the populations of binding-competent states. Our results highlight a previously unrecognized aspect of the "altered self" mechanism of immune recognition and have implications for specificity, cross-reactivity, and antigenicity in cellular immunity.
Highlights
Peptide modulation of MHC flexibility can affect recognition by immune receptors
Less clear is the role of flexibility in the MHC protein; recent observations have indicated that mobility in the MHC can impact T cell receptor (TCR) recognition in a peptide-dependent fashion, the extent of this behavior is unknown
We examined the four peptides studied by Hydrogen/deuterium exchange-mass spectrometry (HDX-MS) as well as gp100T2M, another tight binding peptide whose structure bound to HLA-A2 is available (30)
Summary
Peptide modulation of MHC flexibility can affect recognition by immune receptors. Results: Different peptides alter the flexibility of the MHC protein at sites around the peptide-binding groove. The conformation of the ␣2 helix of the human class I MHC protein HLA-A*0201 (HLA-A2) was shown to undergo a large reorganization upon binding of the A6 TCR (10) This reorganization is dependent on the peptide as it has not been observed upon recognition of other HLA-A2-presented peptides by the same TCR (11, 12). With HLA-A2, the mobility of the region that undergoes a structural change upon binding of the A6 TCR was shown to vary with different peptides (10) This may not be a unique observation as similar effects are believed to contribute to differential T cell recognition of native and modified MART-1 peptides (6), and MHC flexibility can be altered by micropolymorphisms (7, 14, 15). Our findings have implications for immunological specificity, cross-reactivity, and the determinants of antigenicity for class I MHC-presented peptides
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