Store-Operated Ca(2+) Entry in Follicular T Cells Controls Humoral Immune Responses and Autoimmunity.
T follicular helper (Tfh) cells promote affinity maturation of B cells in germinal centers (GCs), whereas T follicular regulatory (Tfr) cells limit the GC reaction. Store-operated Ca(2+) entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels mediated by STIM and ORAI proteins is a fundamental signaling pathway in T lymphocytes. Conditional deletion of Stim1 and Stim2 genes in T cells abolished SOCE and strongly reduced antibody-mediated immune responses following viral infection caused by impaired differentiation and function of Tfh cells. Conversely, aging Stim1Stim2-deficient mice developed humoral autoimmunity with spontaneous autoantibody production due to abolished Tfr cell differentiation in the presence of residual Tfh cells. Mechanistically, SOCE controlled Tfr and Tfh cell differentiation through NFAT-mediated IRF4, BATF, and Bcl-6 transcription-factor expression. SOCE had a dual role in controlling the GC reaction by regulating both Tfh and Tfr cell differentiation, thus enabling protective B cell responses and preventing humoral autoimmunity.
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Martin
M
Vaeth
NYU College of Dentistry, New York University, New York, NY 10010, USA.
Miriam
M
Eckstein
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Patrick J
PJ
Shaw
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
Lina
L
Kozhaya
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Jun
J
Yang
Institute of Pathology, University of Würzburg, 97080 Würzburg, Germany.
Friederike
F
Berberich-Siebelt
Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
Robert
R
Clancy
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
Derya
D
Unutmaz
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: feskes01@nyumc.org.
Stefan
S
Feske
D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071739:Calcium Release Activated Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D018858:Germinal Center / Q000276:immunology*; D056724:Immunity, Humoral; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism; D000071740:ORAI1 Protein / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000378:metabolism; D000071737:Stromal Interaction Molecule 1 / Q000235:genetics / Q000378:metabolism*; D000071738:Stromal Interaction Molecule 2 / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D000099218:Interferon Regulatory Factor-4
D050976:Basic-Leucine Zipper Transcription Factors; D000071739:Calcium Release Activated Calcium Channels; D050835:Interferon Regulatory Factors; D050778:NFATC Transcription Factors; D000071740:ORAI1 Protein; D051560:Proto-Oncogene Proteins c-bcl-6; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D000099218:Interferon Regulatory Factor-4; C431772:Batf protein, mouse; C490010:Bcl6 protein, mouse; C520430:Orai1 protein, mouse
CRAC channel; NFAT; SOCE; STIM1; STIM2; T follicular helper (Tfh) cells; T follicular regulatory (Tfr) cells; calcium