Abstract
B cells can be polarized to express various cytokines. The roles of IFNγ and IL-10, expressed respectively by B effector 1 (Be1) and Bregs, have been established in pathogen clearance, tumor growth, autoimmunity and allograft rejection. However, the in vivo role of B cell IL-4, produced by Be2 cells, remains to be established. We developed B-IL-4/13 iKO mice carrying a tamoxifen-inducible B cell-specific deletion of IL-4 and IL-13. After alloimmunization, B-IL-4/13 iKO mice exhibited decreased IL-4+ Th2 cells and IL-10+ Bregs without impact on Th1, Tregs, or CD8 T cell responses. B-IL-4/13 iKO mice rejected islet allografts more rapidly, even when treated with tolerogenic anti-TIM-1 mAb. In ovalbumin-induced allergic airway disease (AAD), B-IL-4/13 iKO mice had reduced inflammatory cells in BAL, and preserved lung histology with markedly decreased infiltration by IL-4+ and IL-5+ CD4+ T cells. Hence, B cell IL-4 is a major driver of Th2 responses in vivo which promotes allograft survival, and conversely, worsens AAD.
Highlights
While B cells are central to humoral immunity, they play an important role shaping the immune response by presenting antigen, providing T cell co-stimulation, and producing various cytokines [1–9]
In vitro studies first showed that Th2 cells could polarize B cells to produce IL-4, which in turn, amplified Th2 responses [5, 17]
The in vivo role of B cell IL-4 per se was unclear, with studies showing that it was required for Th2 responses with resultant worsening of leishmaniasis, but it was not required for Th2 responses and protection from helminthic infections or pulmonary/ airway inflammation in allergic asthma [7, 20–22]
Summary
While B cells are central to humoral immunity, they play an important role shaping the immune response by presenting antigen, providing T cell co-stimulation, and producing various cytokines [1–9]. Regulatory B cells (Bregs) expressing IL-10 and other inhibitory cytokines, play a critical role maintaining self-tolerance, and can inhibit autoimmunity, allograft and tumor rejection, and anti-microbial responses [3, 9, 12–16]. Lund and colleagues showed that Th1 cells, IFNg, or IL-12, can polarize B cells (termed Be1) to express proinflammatory cytokines such as IFNg and IL-12 [5]. Interaction with Th2 cells or IL-4, polarized B cells (termed Be2) to produce IL-2 and IL-4. B cell IFNg was shown to play an important role in Th1 responses that promote allograft and tumor rejection,
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