B cell–intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans

Abstract

Engagement of cytokine receptors by specific ligands activate Janus kinase–signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21–induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.

CXCR5 Expressing Human Central Memory CD4 T Cells and Their Relevance for Humoral Immune Responses

“…Generally, IL-4 directs GC B cells into memory cells, whereas IL-10 typically steers them toward a PC phenotype (62)(63)(64). Also, IL-21 has recently been recognized as a potent PC differentiation factor in human B cells, rapidly generating plasmablasts from naive, memory, and GC B cells in vitro (41,42,65,66). Furthermore, ICOS-ICOS-L interactions have been shown to play an important Freshly purified CXCR5 + and CXCR5 2 T CM were analyzed by flow cytometry for the expression of CD57, ICOS, PD1, OX40, and CD40L.…”

“…Alternatively, purified CD4 T cells subsets were incubated with allogeneic B cells at a ratio of 1:1 in the presence or absence of T cell activation and expansion beads (Miltenyi Biotech). After 5-6 d of culture, B and T cells were examined for surface phenotype and intracellular cytokine expression as described earlier, and for secretion of IgM, IgG, and IgA by ELISA (30,41,42). Activation of CD4 T cells by different APCs was performed by incubating purified TSST-responsive Vb2 + CD4 T cells for 24 h with autologous cDCs, pDCs, and B cells.…”

“…Matured APCs were then pulsed for 1 h in the presence of 100 ng/ml TSST-1 (Toxin Technology) before purified CD4 T cell subsets were added. Purified B cells were cultured with recombinant CD40L (41,42) alone or together with 100 U/ml human IL-10 (DNAX), 50 ng/ml human IL-21 (PeproTech), 50 ng/ml human IL-17A, or 100 U/ml human IFN-g (PeproTech), and levels of secreted Ig were measured by ELISA as described earlier.…”

Role of IL-21 in Systemic Lupus Erythematosus

“…IL-21R KO mice also formed TFH cells, GC B cells, and isotype switched memory cells and long-lived plasma cells in response to several TD antigens, although IL-21 was important for affinity maturation and reactivation of memory cells [51,52]. Memory B cells are also reduced in the peripheral blood of STAT3 deficient humans, and naïve B cells from these individuals fail to differentiate into plasma cells following stimulation with IL-21 in vitro, providing further evidence that IL-21 may be critical for establishing long-term humoral immunity in humans [56]. Collectively, these studies have shown that IL-21 can influence each stage of an antibody response, however its role depends upon the contextual cues provided to the B cell (ie.…”

L’interleukine-21, une cytokine clé dans le contrôle du VIH et d’autres infections virales chroniques

“…Les souris KO pour l'IL-21R produisent des anticorps de faible affinité ou non spécifiques du virus. En effet, des défauts dans la signalisation impliquant l'IL-21 au niveau des cellules B affaiblissent la réponse des anticorps [21]. Ces données soulignent l'impact général et collectif de l'IL-21 dans la création et l'établissement de réponses immunitaires acquise et humorale lors d'une infection virale chronique.…”