B‐cell‐intrinsic STAT6 signaling controls germinal center formation

Abstract

Infection with helminths and exposure to antigens induce a strong type 2 immune response resulting in the secretion of the cytokines IL-4 and IL-13 by CD4 + T cells and several innate cell types. IL-4 and IL-13 promote class switch recombination to IgG1 and IgE while their role for germinal center (GC) formation is poorly understood. We found a dramatic reduction in the numbers of GC B cells when investigating different type 2 immune responses in IL-4/IL-13-deficient mice. IL-4/IL-13 from T cells locatedAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe cytokines IL-4 and IL-13 contribute to protective immunity against gastrointestinal helminths but also cause pathological side effects seen in atopic diseases. it remains unclear to what extent innate IL-4/IL-13-expressing cell types may also contribute to this process.CSR and affinity maturation of the antibody response to T-dependent antigens usually occurs in germinal centers (GCs). GCs form dynamic structures composed of the light zone where GC B cells undergo selection by interacting with T FH cells and follicular dendritic cells (FDCs) and the dark zone where GC B cells mainly proliferate. The role of the cytokine IL-21 secreted by T FH cells for GC development and subsequent generation of memory B cells is well understood. However, it remains controversial whether other cytokines such as IL-4 and IL-13 might also be critical beyond induction of CSR. Previous studies on the role of IL-4 for GC formation led to inconclusive results. Depending on the kind of adjuvant used IL-4-deficient mice were reported to develop either a normal [1,2], enhanced [3], or diminished [4,5] GC response in LNs after OVA immunization.To conclusively address the role of IL-4/IL-13 for B-cell responses, we used different stimulation protocols to generate type 1 and type 2 immune responses. We found that absence of IL-4/IL-13 impairs formation of GC during type 2 immune responses such as Nippostrongylus brasiliensis (Nb) infection, immunization with OVA/alum or sheep red blood cells (SRBCs) but not during type 1 immune response to lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV). Using conditional IL-4/IL-13-deficient (4-13Tko) mice, we identified T cells to be the essential source of IL-4/IL-13 for the GC response. Our results further indicate that IL-4/IL-13 secretion from T cells localized outside B-cell follicles is sufficient for GC formation and IgE-CSR and that STAT6 signaling in B cells is required for GC formation. Results T-cell-derived IL-4/IL-13 promotes GC formation during type 2 immunityWe used infection with Nb to induce a strong type 2 immune response in order to define the roles of IL-4/IL-13 in the activation of B cells in secondary lymphoid organs. Histological analysis of draining LNs on day 12 after Nb infection revealed that GC formation was severely impaired in Nb-infected IL-4/IL-13-deficient (4-13ko) mice compared to WT mice (Fig. 1A). By analyzing GC B c...

Glucocorticoid-induced leucine zipper (GILZ) inhibits B cell activation in systemic lupus erythematosus

“…Multiple genes that promote B cell germinal centre entry and persistence were upregulated in mature naïve B cells lacking GILZ, including Bak1 and Bax 53 54, Mcl-1 ,55 56 Id3 ,57 c-Myc ,54 Tlr9 ,58 Stat6 ,59 Socs3 34 and MyD88 60. Thus, naïve B cells lacking GILZ bear a transcriptional profile that may predispose towards activation, survival and germinal centre entry.…”

Type 2 Cytokine Responses: Regulating Immunity to Helminth Parasites and Allergic Inflammation

“…In addition to antibody production, B cells have been proposed to contribute to T H 2 polarization by expression of co-stimulatory molecules such as OX40L and B7 after infection with N. brasiliensis and H. polygyrus (31, 32). In return, T-cell derived IL-4 and IL-13 signal through STAT6 on B cells, promoting the generation of germinal center responses(33). This pathway and its clinical importance are compressively described in several review articles (29, 34, 35).…”

Histone H3k9 and H3k27 Acetylation Regulates IL‐4/STAT6‐Mediated Igε Transcription in B Lymphocytes

“…Furthermore, STAT6 is a critical regulator in IL-4-mediated B-cell differentiation. Previous work has shown that B cells from mice lacking STAT6 failed to produce significant amounts of IgE and IgG1 after infection with the nematode parasites (Raia et al, 2011;Turqueti-Neves et al, 2014). The binding sites of STAT6 have been found in the target regions of a variety of IL-4-mediated genes, including CD23 (Cooper et al, 2012), IL-4R (Jenkins et al, 2013), eotaxin-1 (Waddell et al, 2013), eotaxin-3 (Nakayama et al, 2010), FIZZ1 (Dasgupta et al, 2011), and in Ig germline e (Lu et al, 2007) promoters.…”