Autoimmune demyelinating disease results from the combined effects of T cell affinity and increased bond lifetime for self antigen.

Abstract

Abstract A fundamental question for autoimmunity is how T cells become activated to attack self in the periphery. Antigen recognition by T cells is often characterized by affinity, defined as the strength and therefore likelihood of interaction between TCR and peptide:MHC (pMHC), with the assumption that higher affinity T cells will be more pathogenic. However, our analyses of polyclonal and monoclonal CD4+ T cells reveal a wide range of affinities for myelin oligodendrocyte glycoprotein (MOG) responsive T cells in EAE. We argue a finer degree of detail than affinity as the sole predictor of function because high and low affinity T cells promote paralytic disease. Affinity for antigen becomes a key factor in the kinetics of T cell activation, but is just one parameter. T cells also generate dynamic forces during this process and force adds a level of mechanical regulation to the TCR-pMHC bond by shortening or enhancing bond lifetimes. This is important because the lifetime contributes to functional potency of the response. For the first time, we report the bond lifetime of MOG specific T cells under applied force and demonstrate that upon activation, the T cells biophysically change, exhibiting similar lifetimes regardless of high or low affinity designation. This is novel because high, not low, affinity TCRs are predicted to exhibit long lifetimes. Comparatively, activated myelin specific T cells generate bond lifetimes similar to cells with foreign antigen specificity. In all, our data support a kinetic proofreading model of T cell activation linking antigen discrimination, actin remodeling and availability of intracellular chemical messengers where with time, high and low affinity T cells are essentially equipotent contributors to autoimmunity.