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

Journal article

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.

Authors: Schubert, D; Gordo, S; Sabatino, J; Vardhana, S; Gagnon, E

• Journal: Journal of experimental medicine
• Volume: 209
• Issue: 2
• Pages: 335-352
• Publication date: 2012-02-01
• DOI: 10.1084/jem.20111485
• EISSN: 1540-9538
• ISSN: 0022-1007
• Language: English
• Keywords: CD4-Positive T-Lymphocytes; Intercellular Adhesion Molecule-1; Receptors, Antigen, T-Cell; Multiple Sclerosis; Phosphorylation; Animals; HLA Antigens; Immunoblotting; Mice, Transgenic; Immunological Synapses; Cell Movement; Mice; Humans; Microscopy, Fluorescence; Diabetes Mellitus, Type 1; Signal Transduction; Microscopy, Confocal