title: The development and survival but not function of follicular B cells is dependent on IL-7Rα Tyr449 signaling.
abstract: IL-7 is a critical cytokine for lymphocyte development. Recent work has highlighted critical roles for IL-7 signaling in mature T cell homeostasis and function, but its role in B cells is less well characterized. Using a knock-in mouse possessing a Tyr to Phe mutation at position 449 (IL-7Rα(449F/449F) mice) within the cytoplasmic SH2-binding motif of IL-7Rα, we evaluated the role of IL-7Rα Y449 motif in spleen B cells. IL-7Rα(449F/449F) mice had reduced numbers and increased death of follicular B cells compared to WT, but had significantly more follicular cells than IL-7Rα(-/-). The death of IL-7Rα(449F/449F) follicular cells was not due to a failure to respond to BAFF or lower levels of BAFF, a critical B cell survival factor. Marginal zone B cells were unaffected by the IL-7Rα(449F/449F) mutation. Any role for TSLP was ruled out, as TSLPR(-/-) mice had an identical B cell phenotype to wild-type mice. Bone marrow chimeras and the absence of IL-7Rα on B cells suggested that IL-7 did not directly regulate mature B cells, but that an IL-7-responsive cell was influencing B cells. IL-7 was also critical at the checkpoint between the T1 and T2 stages in the spleen. IL-7Rα(-/-) mice fail to develop T2 cells, but IL-7Rα(449F/449F) show a reduction compared to WT but not complete absence of T2 cells. We also tested the functional responses of IL-7Rα(449F/449F) to antigens and infection and found no difference in antibody responses to T-dependent or T-independent antigens, or to Influenza/A. IL-7 was important for generation of antibody responses to the intestinal worm H. polygyrus and for naive levels of IgA. Taken together, this suggests that IL-7 regulates follicular B cell numbers and survival in a cell-extrinsic manner, via a bone-marrow derived cell, but is not critical for antibody production outside the gut.
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Patton
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
authors.forename: Adam W
authors.initials: AW
authors.lastname: Plumb
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Redpath
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Osborne
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
authors.forename: Georgia
authors.initials: G
authors.lastname: Perona-Wright
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada ; Department of Zoology, University of British Columbia, Vancouver, Canada.
authors.forename: Ninan
authors.initials: N
authors.lastname: Abraham
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000956:Antigens, Viral / Q000097:blood; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002470:Cell Survival; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D007074:Immunoglobulin G / Q000097:blood; D009980:Influenza A virus / Q000276:immunology; D015851:Interleukin-7 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D054730:Protein Interaction Domains and Motifs; D020395:Receptors, Interleukin-7 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; D053264:B-Cell Activating Factor; D016207:Cytokines; D007074:Immunoglobulin G; D015851:Interleukin-7; D020395:Receptors, Interleukin-7; C505720:Tnfsf13b protein, mouse; C415350:interleukin-7 receptor, alpha chain; D000094632:Thymic Stromal Lymphopoietin