The Development and Survival but Not Function of Follicular B Cells Is Dependent on IL-7Rα Tyr449 Signaling
Patton, Daniel T.
Plumb, Adam W.
Redpath, Stephen A.
Osborne, Lisa C.
- Publisher: Public Library of Science
Humoral Immunity | Research Article | Biology | Hematologic Cancers and Related Disorders | Immunity to Infections | Lymphomas | Immune Cells | Medicine | Immunity | Bone Marrow | Hematology | B Cells | Antibody-Producing Cells | Immune Response | Immune System | Immunoregulation | Cytokines | Immunology
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-7Rα449F/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-7Rα449F/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-7Rα449F/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-7Rα449F/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-7Rα449F/449F show a reduction compared to WT but not complete absence of T2 cells. We also tested the functional responses of IL-7Rα449F/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.