title: The tetraspanin protein CD37 regulates IgA responses and anti-fungal immunity.
abstract: Immunoglobulin A (IgA) secretion by plasma cells in the immune system is critical for protecting the host from environmental and microbial infections. However, the molecular mechanisms underlying the generation of IgA(+) plasma cells remain poorly understood. Here, we report that the B cell-expressed tetraspanin CD37 inhibits IgA immune responses in vivo. CD37-deficient (CD37-/-) mice exhibit a 15-fold increased level of IgA in serum and significantly elevated numbers of IgA(+) plasma cells in spleen, mucosal-associated lymphoid tissue, as well as bone marrow. Analyses of bone marrow chimeric mice revealed that CD37-deficiency on B cells was directly responsible for the increased IgA production. We identified high local interleukin-6 (IL-6) production in germinal centers of CD37-/- mice after immunization. Notably, neutralizing IL-6 in vivo reversed the increased IgA response in CD37-/- mice. To demonstrate the importance of CD37-which can associate with the pattern-recognition receptor dectin-1-in immunity to infection, CD37-/- mice were exposed to Candida albicans. We report that CD37-/- mice are evidently better protected from infection than wild-type (WT) mice, which was accompanied by increased IL-6 levels and C. albicans-specific IgA antibodies. Importantly, adoptive transfer of CD37-/- serum mediated protection in WT mice and the underlying mechanism involved direct neutralization of fungal cells by IgA. Taken together, tetraspanin protein CD37 inhibits IgA responses and regulates the anti-fungal immune response.
authors.affiliation: Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Annemiek B
authors.initials: AB
authors.lastname: van Spriel
authors.forename: Mariam
authors.initials: M
authors.lastname: Sofi
authors.forename: Kate H
authors.initials: KH
authors.lastname: Gartlan
authors.forename: Alie
authors.initials: A
authors.lastname: van der Schaaf
authors.forename: Ineke
authors.initials: I
authors.lastname: Verschueren
authors.forename: Ruurd
authors.initials: R
authors.lastname: Torensma
authors.forename: Reinier A P
authors.initials: RA
authors.lastname: Raymakers
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Loveland
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wright
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D018858:Germinal Center / Q000276:immunology; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000096:biosynthesis / Q000276:immunology*; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009181:Mycoses / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059470:Tetraspanins
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; C504565:Cd37 protein, mouse; D006023:Glycoproteins; D007070:Immunoglobulin A; D015850:Interleukin-6; D059470:Tetraspanins