Abstract
CD4+ and CD8+ αβ T cell antigen recognition is determined by the interaction between the TCR Complementarity Determining Region (CDR) loops and the peptide-presenting MHC complex. These T cells are known for their ability to recognize multiple pMHC complexes, and for a necessary promiscuity that is required for their selection and function in the periphery. Crystallographic studies have previously elucidated the role of structural interactions in TCR engagement, but our understanding of the dynamic process that occurs during TCR binding is limited. To better understand the dynamic states that exist for TCR CDR loops in solution, and how this relates to their states when in complex with pMHC, we simulated the 2C T cell receptor in solution using all-atom molecular dynamics in explicit water and constructed a Markov State Model for each of the CDR3α and CDR3β loops. These models reveal multiple metastable states for the CDR3 loops in solution. Simulation data and metastable states reproduce known CDR3β crystal conformations, and reveal several novel conformations suggesting that CDR3β bound states are the result of search processes from nearby pre-existing equilibrium conformational states. Similar simulations of the invariant, Type I Natural Killer T cell receptor NKT15, which engages the monomorphic, MHC-like CD1d ligand, demonstrate that iNKT TCRs also have distinct states, but comparatively restricted degrees of motion.
Highlights
T cells are key components of the adaptive immune system that recognize processed antigens presented on cell surfaces by major histocompatibility complex (MHC) and MHC-like proteins via T cell receptors (TCRs)
We studied the conformational changes of the CDR3α and CDR3β loops individually by analyzing their backbone dihedral angles under the time-lagged independent component analysis (tICA) decomposition
The tICA decomposition is similar to Principal Component Analysis (PCA), in that it looks for linear combinations of degrees of freedom that better describe the data while holding each combination in the set to be independent of the others
Summary
T cells are key components of the adaptive immune system that recognize processed antigens presented on cell surfaces by major histocompatibility complex (MHC) and MHC-like proteins via T cell receptors (TCRs). CD4+ and CD8+ αβ TCRs recognize antigenic peptides bound to MHC proteins (pMHC), provoking an adaptive immune response to infection, cancer and dysregulated tissue. CD4+/CD8+ αβ TCRs show both specific and degenerate recognition characteristics. Thymic-selection and homeostatic maintenance in the periphery require that TCRs recognize MHC. To provide effective coverage of possible antigens TCRs must be cross-reactive, which has been experimentally demonstrated (Mason, 1998; Wilson et al, 2004; Sewell, 2012). To avoid autoimmunity TCRs must distinguish self-peptides from non-self antigenic
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