Molecular mimicry is the underlying mechanism that allows the restricted TCR repertoire its cross-reactivity, accommodating the vast potential antigen universe that an individual may encounter. Expanding beyond this mechanism, Riley et al. demonstrate through biochemical, modeling, and structural determinations that cross-reactivity can occur through a shift in the position in the MHC groove and a C-terminal extension of a cross-reactive peptide relative to the typical peptide:MHC binding position while maintaining the key interactions between the TCR and HLA molecule.
T cell receptor cross-reactivity allows a fixed T cell repertoire to respond to a much larger universe of potential antigens. Recent work has emphasized the importance of peptide structural and chemical homology, as opposed to sequence similarity, in T cell receptor cross-reactivity. Surprisingly, though, T cell receptors can also cross-react between ligands with little physiochemical commonalities. Studying the clinically relevant receptor DMF5, we demonstrate that cross-recognition of such divergent antigens can occur through mechanisms that involve heretofore unanticipated rearrangements in the peptide and presenting MHC protein, including binding-induced peptide register shifts and extensions from MHC peptide binding grooves. Moreover, cross-reactivity can proceed even when such dramatic rearrangements do not translate into structural or chemical molecular mimicry. Beyond demonstrating new principles of T cell receptor cross-reactivity, our results have implications for efforts to predict and control T cell specificity and cross-reactivity and highlight challenges associated with predicting T cell reactivities.
Author Info: (1) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA. (2) De
Author Info: (1) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA. (2) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA. (3) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. (4) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. (5) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. (6) Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA. (7) Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA. (8) Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA. (9) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. (10) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA. brian-baker@nd.edu. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA. brian-baker@nd.edu.
