Self-reactive human CD4 T cell clones form unusual immunological synapses.
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.
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
David A
DA
Schubert
Susana
S
Gordo
Joseph J
JJ
Sabatino
Santosh
S
Vardhana
Etienne
E
Gagnon
Dhruv K
DK
Sethi
Nilufer P
NP
Seth
Kaushik
K
Choudhuri
Helena
H
Reijonen
Gerald T
GT
Nepom
Brian D
BD
Evavold
Michael L
ML
Dustin
Kai W
KW
Wucherpfennig
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D054992:Immunological Synapses / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009103:Multiple Sclerosis / Q000276:immunology*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*
D006680:HLA Antigens; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1