Follicular helper T cells are required for systemic autoimmunity.
Production of high-affinity pathogenic autoantibodies appears to be central to the pathogenesis of lupus. Because normal high-affinity antibodies arise from germinal centers (GCs), aberrant selection of GC B cells, caused by either failure of negative selection or enhanced positive selection by follicular helper T (T(FH)) cells, is a plausible explanation for these autoantibodies. Mice homozygous for the san allele of Roquin, which encodes a RING-type ubiquitin ligase, develop GCs in the absence of foreign antigen, excessive T(FH) cell numbers, and features of lupus. We postulated a positive selection defect in GCs to account for autoantibodies. We first demonstrate that autoimmunity in Roquin(san/san) (sanroque) mice is GC dependent: deletion of one allele of Bcl6 specifically reduces the number of GC cells, ameliorating pathology. We show that Roquin(san) acts autonomously to cause accumulation of T(FH) cells. Introduction of a null allele of the signaling lymphocyte activation molecule family adaptor Sap into the sanroque background resulted in a substantial and selective reduction in sanroque T(FH) cells, and abrogated formation of GCs, autoantibody formation, and renal pathology. In contrast, adoptive transfer of sanroque T(FH) cells led to spontaneous GC formation. These findings identify T(FH) dysfunction within GCs and aberrant positive selection as a pathway to systemic autoimmunity.
Linterman
Michelle A
MA
Division of Immunology and Genetics, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.
Rigby
Robert J
RJ
Wong
Raphael K
RK
Yu
Di
D
Brink
Robert
R
Cannons
Jennifer L
JL
Schwartzberg
Pamela L
PL
Cook
Matthew C
MC
Walters
Giles D
GD
Vinuesa
Carola G
CG
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D018106:CD28 Antigens / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D018858:Germinal Center / Q000166:cytology* / Q000276:immunology; D006579:Heterozygote; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins / Q000172:deficiency; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D051379:Mice; D010641:Phenotype; D051560:Proto-Oncogene Proteins c-bcl-6; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000637:transplantation; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000098546:Interleukin-21
D000945:Antigens, Differentiation, T-Lymphocyte; D001323:Autoantibodies; C490010:Bcl6 protein, mouse; D018106:CD28 Antigens; D004268:DNA-Binding Proteins; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins; D051560:Proto-Oncogene Proteins c-bcl-6; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D000098546:Interleukin-21