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Abstract
Understanding the basis of the binding of a T cell receptor (TR) to the peptide-MHC (pMHC) complex is essential due to the vital role it plays in adaptive immune response. We describe the use of computed binding (free) energy (BE), TR paratope, pMHC epitope, molecular surface electrostatic potential (MSEP) and calculated TR docking angle (θ) to analyse 61 TR/pMHC crystallographic structures to comprehend TR/pMHC interaction. In doing so, we have successfully demonstrated a novel/rational approach for θ calculation, obtained a linear correlation between BE and θ without any “codon” or amino acid preference, provided an explanation for TR ability to scan many pMHC ligands yet specifically bind one, proposed a mechanism for pMHC recognition by TR leading to T cell activation and illustrated the importance of the peptide in determining TR specificity, challenging the “germline bias” theory.
Highlights
For maximal immunological protection against a multitude of pathogens, the adaptive immune response in higher jawed vertebrates causes major histocompatibility complexes (MHC) or human leukocyte antigens (HLA) in human, to bind antigenic peptides (p) and present them as peptide-MHC complexes on the surface of antigen-presenting cells (APC), for recognition by T cell receptors (TR) [1]. This TR/pMHC interaction is relatively feeble compared to other important interactions between the molecules of the immune system [2], yet strong enough to trigger TR mediated activation of T cells, thereby eliciting an immediate immune response to either destroy infected cells directly or activate other immune system cells like B cells and macrophages to carry out the immune response
The two constant domains (Ca and Cb) of the TR are linked to variable domains (Va and Vb encoded by rearranged variable (V), diversity (D) and joining (J) genes, V-J and V-D-J genes, respectively), whose CDR1, CDR2 and CDR3 loops recognize pMHC [5]
Garcia and co-workers [4] have provided highly influential hypotheses using a dataset of 20 TR/pMHC structures, implying that the contacts between CDR1 and CDR2 loops of TR variable domains and MHC helices are germline-encoded leading to the conclusion that TR/pMHC binding is peptide independent
Summary
For maximal immunological protection against a multitude of pathogens, the adaptive immune response in higher jawed vertebrates causes major histocompatibility complexes (MHC) or human leukocyte antigens (HLA) in human, to bind antigenic peptides (p) and present them as peptide-MHC (pMHC) complexes on the surface of antigen-presenting cells (APC), for recognition by T cell receptors (TR) [1]. Using in vitro immuno-assays, researchers have previously reported that weak BE between TR and pMHC complexes ascribe weak agonistic (T cell activating) properties to the pMHC complexes and vice versa [18,19,20] This inference is based on the underlying idea that the strength of TR binding to pMHC plays a vital role in stabilizing the half-life of the TR/pMHC complex, resulting in T cell signalling or activation. The results of MSEP similarity calculation at the pMHC interface along with our TR paratope and pMHC epitope analyses suggest a weakening of ‘‘germline bias’’ theory over a larger dataset and highlight the significant role played by the peptide in determining TR specificity, thereby, providing an explanation to our second query.
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