Self-reactive human CD4 T cell clones form unusual immunological synapses

• Authors: David A. Schubert, Dana-Farber Cancer Institute; Susana Gordo, Dana-Farber Cancer Institute; Joseph J. Sabatino, Emory University; Santosh Vardhana, Helen L. and Martin S. Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine; Etienne Gagnon, Dana-Farber Cancer Institute; Dhruv K. Sethi, Dana-Farber Cancer Institute; Nilufer P. Seth, Dana-Farber Cancer Institute; Kaushik Choudhuri, Helen L. and Martin S. Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine; Helena Reijonen, Benaroya Research Institute at Virginia Mason; Gerald T. Nepom, Benaroya Research Institute at Virginia Mason; Brian Evavold, Emory University; Michael L. Dustin, Helen L. and Martin S. Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine; Kai W. Wucherpfennig, Dana-Farber Cancer Institute
• Journal Title: Journal of Experimental Medicine
• Volume: Volume 209, Number 2
• Publisher: Rockefeller University Press | 2012-02-13, Pages 335-352
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1084/jem.20111485
• Subjects: Health Sciences, Immunology; Biology, Microbiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Immunology; Medicine, Research & Experimental; Research & Experimental Medicine; IMMUNOLOGY; MEDICINE, RESEARCH & EXPERIMENTAL; SUPRAMOLECULAR ACTIVATION CLUSTER; THYMIC EPITHELIAL-CELLS; KINASE-C-THETA; PEPTIDE-MHC; RECEPTOR MICROCLUSTERS; ADHESION MOLECULES; NEGATIVE SELECTION; ACTIN CYTOSKELETON; IN-VITRO; HLA-DM

Abstract

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.