Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Recognition of self-peptide-MHC (pMHC) complexes by CD4 T cells plays an important role in the pathogenesis of many autoimmune diseases. We analyzed formation of immunological synapses (IS) in self-reactive T cell clones from patients with multiple sclerosis and type 1 diabetes. All self-reactive T cells contained a large number of phosphorylated T cell receptor (TCR) microclusters, indicative of active TCR signaling. However, they showed little or no visible pMHC accumulation or transport of TCR-pMHC complexes into a central supramolecular activation cluster (cSMAC). In contrast, influenza-specific T cells accumulated large quantities of pMHC complexes in microclusters and a cSMAC, even when presented with 100-fold lower pMHC densities. The self-reactive T cells also maintained a high degree of motility, again in sharp contrast to virus-specific T cells. 2D affinity measurements of three of these self-reactive T cell clones demonstrated a normal off-rate but a slow on-rate of TCR binding to pMHC. These unusual IS features may facilitate escape from negative selection by self-reactive T cells encountering very small amounts of self-antigen in the thymus. However, these same features may enable acquisition of effector functions by self-reactive T cells encountering large amounts of self-antigen in the target organ of the autoimmune disease.

Original publication

DOI

10.1084/jem.20111485

Type

Journal article

Journal

J Exp Med

Publication Date

13/02/2012

Volume

209

Pages

335 - 352

Keywords

Animals, CD4-Positive T-Lymphocytes, Cell Movement, Diabetes Mellitus, Type 1, HLA Antigens, Humans, Immunoblotting, Immunological Synapses, Intercellular Adhesion Molecule-1, Mice, Mice, Transgenic, Microscopy, Confocal, Microscopy, Fluorescence, Multiple Sclerosis, Phosphorylation, Receptors, Antigen, T-Cell, Signal Transduction