In vitro, Sema4A-Fc has been reported to enhance T-cell activation, proliferation, and interleukin 2 (IL-2) production, whereas anti-Sema4A antibody (Ab) inhibited allogeneic T-cell/DC mixed lymphocyte reaction. 12, 13, 14 These interactions have been shown to play important roles in several physiological and pathological conditions such as angiogenesis, 14 neuron growth cone collapse, 13 and retina formation. 10, 11 In nonlymphoid tissues, Sema4A functionally interacts with plexin family members, namely Plexin D1 and Plexin B1. 10, 11 Sema4A functionally interacts with Tim-2 (T-cell immunoglobulin and mucin domain 2) expressed on T cells, T helper type 2 (Th2) cells predominantly. 10 It was reported to act as a costimulatory molecule, enhancing the activation and differentiation of T cells in vitro and potentiating the generation of antigen (Ag)-specific T cells in vivo. 9 Recently, Sema4A was located in the lymphoid tissues where its expression was preferentially restricted to the antigen-presenting cells (APCs) such as dendritic cells (DCs) and B cells. Semaphorin 4A (Sema4A) belongs to a large family of secreted and membrane-bound glycoproteins that were originally found to be expressed in the nervous system and function as axon guidance molecules. 5, 6 Therefore, novel molecular targets are being investigated 7 and novel approaches are being developed 8 that may have a profound impact on improving the diagnostic, prevention, and treatment of the allergic asthmatic diseases. Moreover, many side effects of these medicines, which involve bone, metabolic, and cardiovascular systems, also limit their efficacy. 3, 4 Despite a number of currently used therapies such as glucocorticoids, β-agonists, antihistamines, phosphodiesterase inhibitors, and anticholinergic agents, many patients continue to suffer from the disease exacerbation. 1, 2 The pathophysiology of asthma is characterized by eosinophil-rich inflammatory cell infiltrates, mucus hypersecretion, airway hyperresponsiveness, and airway wall remodeling. The incidence of asthma is on the rise worldwide, resulting in the increased morbidity and mortality and making it an economic burden to society. These data provide a new insight into Sema4A biology and define Sema4A as an important regulator of Th2-driven lung pathophysiology. Generated bone marrow chimeras showed an equal importance of both lung-resident cell and inflammatory cell Sema4A expression in optimal disease regulation. T-cell proliferation and IL-13 productions in OVA 323–339-restimulated Sema4A −/− cell cultures were upregulated. In vivo allergen-primed Sema4A −/− CD4+ T cells were more effective in transferring T helper type 2 (Th2) response to naive mice as compared with WT CD4+ T cells. This enhanced inflammatory response was associated with a selective increase in bronchoalveolar lavage (BAL) interleukin 13 (IL-13) content, augmented airway hyperreactivity, and lower regulatory T cell (Treg) numbers.

We observed a selective increase in eosinophilic airway infiltration accompanied by bronchial epithelial cell hyperplasia in allergen-treated Sema4A −/− mice relative to WT mice.

To define the role of semaphorin 4A (Sema4A) in allergic response, we employed Sema4A −/− and wild-type (WT) mice in the experimental model of ovalbumin (OVA)-induced allergic airway inflammation.

Flowjo envoy