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

• Type of Material: Article
• 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
• Language: English
• Date: 2012-02-13
• Publisher: Rockefeller University Press
• Publication Version: Final Published Version
• Copyright Statement: © 2012 Schubert et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1084/jem.20111485
• Title of Journal or Parent Work: Journal of Experimental Medicine
• ISSN: 0022-1007
• Volume: 209
• Issue: 2
• Start Page: 335
• End Page: 352
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health (PO1 AI045757 to K.W. Wucherpfennig and M.L. Dustin) and by postdoctoral fellowships from the Cancer Research Institute (to D.A. Schubert and E. Gagnon), the Ernst-Schering Foundation (to D.A. Schubert), the Generalitat de Catalunya – AGAUR (to S. Gordo), and the National Multiple Sclerosis Society (to D.K. Sethi).
• Keywords: Medicine, Research & Experimental; ACTIN CYTOSKELETON; SUPRAMOLECULAR ACTIVATION CLUSTER; Science & Technology; PEPTIDE-MHC; RECEPTOR MICROCLUSTERS; KINASE-C-THETA; IMMUNOLOGY; Research & Experimental Medicine; ADHESION MOLECULES; MEDICINE, RESEARCH & EXPERIMENTAL; HLA-DM; IN-VITRO; NEGATIVE SELECTION; THYMIC EPITHELIAL-CELLS; Life Sciences & Biomedicine; Immunology
• Research Categories: Biology, Microbiology; Health Sciences, Immunology

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.