Dynamical footprint of cross-reactivity in a human autoimmune T-cell receptor

Amit Kumar,Francesco Delogu

doi:10.1038/srep42496

Abstract

The present work focuses on the dynamical aspects of cross-reactivity between myelin based protein (MBP) self-peptide and two microbial peptides (UL15, PMM) for Hy.1B11 T-cell receptor (TCR). This same TCR was isolated from a patient suffering from multiple sclerosis (MS). The study aims at highlighting the chemical interactions underlying recognition mechanisms between TCR and the peptides presented by Major Histocompatibility Complex (MHC) proteins, which form a crucial component in adaptive immune response against foreign antigens. Since the ability of a TCR to recognize different peptide antigens presented by MHC depends on its cross-reactivity, we used molecular dynamics methods to obtain atomistic detail on TCR-peptide-MHC complexes. Our results show how the dynamical basis of Hy.1B11 TCR’s cross-reactivity is rooted in a similar bridging interaction pattern across the TCR-peptide-MHC interface. Our simulations confirm the importance of TCR CDR3α E98 residue interaction with MHC and a predominant role of P6 peptide residue in MHC binding affinity. Altogether, our study provides energetic and dynamical insights into factors governing peptide recognition by the cross-reactive Hy.1B11 TCR, found in MS patient.

Highlights

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system[1], affecting more than 2.5 million people worldwide[2]
We found a new interaction between another T-cell receptor (TCR) loop CDR2β D55 residue and human leukocyte antigen (HLA)-DQ1α K39 residue, located outside the peptide-binding groove, to constitute a conserved anchor point for docking TCR on to major histocompatibility complex (MHC) class II protein
The persistent hydrogen bonded (H-bond) interaction evaluated between the HLA-DQ1 bound peptide residues and TCR residues survived for than 60% of the molecular dynamics (MD) simulations

Summary

Introduction

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system[1], affecting more than 2.5 million people worldwide[2]. MS involves an abnormal response of the human body’s immune system directed against brain and spinal cord. The exact antigen that immune system cells are sensitized to attack has not been recognized yet, and this leads many experts to consider MS as an “immune-mediated” process, rather than an “autoimmune” disease. T-cells form a subset of lymphocytes, critical for providing an adaptive immune response against invading pathogens[16]. The T-cell receptor (TCR) at the surface of T lymphocytes is a complex of integral membrane proteins that participates in the activation of T-cells in response to an antigen[17]. Initiates positive and negative cascades leading to T-cell activation, differentiation, proliferation and, to a specific immune response to the invading pathogen[19,20]

Methods

Results

Conclusion