Invariant NKT cells limit activation of autoreactive CD1d-positive B cells.
Faulty activation of autoreactive B cells is a hallmark of autoimmune diseases like systemic lupus erythematosus (SLE). An important feature restricting activation of autoreactive B cells is efficient removal of apoptotic material. Mounting evidence also connects a primary defect in invariant natural killer T (iNKT) cells to autoimmune disease development. However, exactly how this unconventional T cell subset is involved remains to be defined. Here, we identify a suppressive role for iNKT cells in a model where autoantibody production is triggered by an increased load of circulating apoptotic cells, resembling the situation in SLE patients. Absence or reduction of iNKT cells as well as absence of CD1d-expression on B cells, needed for direct iNKT-B cell interaction, leads to increased autoreactive B cell activation and symptoms of disease. The suppression mediated by the iNKT cells is observed before B cell entry into germinal centers and can be rescued by transferring iNKT cells to deficient mice. This links iNKT cells to handling of dying cells and identifies a novel peripheral tolerance checkpoint relevant for autoimmune disease. Thus, these observations connect two clinical observations in SLE patients previously considered to be unrelated and define a new target for immunotherapy.
Wermeling
Fredrik
F
Department of Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
Lind
Sara M
SM
Jordö
Emilie Domange
ED
Cardell
Susanna L
SL
Karlsson
Mikael C I
MC
D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000235:genetics; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000502:physiology
D055610:Antigens, CD1d; D016207:Cytokines