Identification of Semaphorin 4B as a Negative Regulator of Basophil-Mediated Immune Responses

Abstract

Basophils are strong mediators of Th2 responses during helminthic infections. Recently, basophils were shown to function as APCs and promote both Th2 skewing and humoral memory responses. However, the mechanisms that regulate basophils are still unclear. In this article, we show that a class IV semaphorin, Sema4B, negatively regulates basophil functions through T cell–basophil contacts. In a screen to identify semaphorins that function in the immune system, we determined that Sema4B is expressed in T and B cells. Interestingly, Sema4B−/− mice had considerably increased serum IgE levels despite normal lymphocyte and dendritic cell functions. Recombinant Sema4B significantly inhibited IL-4 and IL-6 production from basophils in response to various stimuli, including IL-3, papain, and FcεRI cross-linking. In addition, T cell-derived Sema4B, which accumulated at contact sites between basophils and CD4+ T cells, suppressed basophil-mediated Th2 skewing, suggesting that Sema4B regulates basophil responses through cognate cell–cell contacts. Furthermore, Sema4B−/− mice had enhanced basophil-mediated memory IgE production, which was abolished by treating with an anti-FcεRIα Ab. Collectively, these results indicate that Sema4B negatively regulates basophil-mediated Th2 and humoral memory responses.

Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function

“…Notch 1 (a validated target of miR-34a) has been implicated as an important mediator of cardiac repair and regeneration after MI (25). Bcl6 is known to protect mature cardiomyocytes from inflammation (27), and Sema4b has been shown to inhibit IL-6 production by basophils (36). Sema4b was also positively correlated with systolic function in an MI setting (Fig.…”

Diverse roles for semaphorin−plexin signaling in the immune system

“…Sema4B inhibits interleukin (IL)-4 production from basophils, and T cell derived Sema4B suppresses basophil-mediated Th2 skewing. Furthermore, Sema4b À/À mice have enhanced basophil-mediated memory IgE production [24]. Thus, Sema4B negatively regulates basophilmediated Th2 and humoral memory responses.…”

“…Membrane-associated semaphorins play a role in regulating immune homeostasis and are involved in pathogenesis of several diseases in mouse models [14,24]. The structure of semaphorin-plexin complexes has recently been determined [25][26][27], which may be useful to develop small compounds and antibodies to target these molecules.…”

“…Sema4B, which contains a PDZ-binding motif in its cytoplasmic tail, is expressed by T cells and B cells and negatively regulates basophil function by promoting T cellÀbasophil interactions [24]. Basophils are strong mediators of Th2 skewing and humoral memory responses, and secret IL-4 during helminthic infections [57].…”

Mast Cells, Basophils and Mucosal Immunity

“…Interactions between basophils and DC migrating to the lymph nodes following antigen exposure is also important for basophil activation and Th 2 differentiation (Tang et al, 2010). In some settings, T cell-basophil cognate interactions may decrease the ability of basophils to induce Th 2 polarization (Nakagawa et al, 2011). However, the role of basophils in Th 2 differentiation is not universal, as administration of house dust mite extracts to mice also leads to accumulation of basophils in draining lymph nodes, but elimination of basophils has little effect on development of Th 2 responses to these allergens (Hammad et al, 2010).…”