Semaphorins belong to a family of membrane-bound and secreted molecules that regulate the functional activity of axons in the nervous system. Sema4A and Sema4D were the first semaphorins also found to be expressed in immune cells and were, therefore, termed “immune semaphorins”. It is known that Sema4A has three functional receptors, namely Plexin D1, Plexin B1, and Tim-2, whereas Sema4D binds to Plexin B1 and CD72. Recent studies suggest that immune semaphorins play critical roles in many physiological and pathological processes and such. In this review, we summarize the current knowledge on the biology of neuroimmune semaphorins and their corresponding receptors, their distribution in organs and tissues, function in the immune response, and critical regulatory roles in various diseases.

Semaphorin 4A belongs to a family of secreted and membrane-bound glycoproteins which were originally found to be expressed in the nervous system and function as axon guidance molecules. Recent studies identified Sema4A to be expressed and function in the immune system. An abundant Sema4A expression was found on APC but not on resting T cells. The expression was upregulated with corresponding cell activation. Sema4A on APC has been reported to enhance activation and differentiation of T cells in vitro and generation of Ag-specific T cells in vivo. We hypothesized that Sema4A plays a critical regulatory role in allergic airway response. To test our hypothesis, we employed Sema4A-/- and WT mice in the well-defined mouse model of OVA-induced experimental asthma. We observed a significant increase in eosinophilic airway infiltration accompanied by bronchial epithelial cell hyperplasia in allergen-treated Sema4A-/- mice as compared to similarly treated WT mice. This enhanced inflammatory response was associated with a selective increase in BAL IL-13 content. Surprisingly, an augmented AHR was detected in both PBS- and OVA-treated Sema4A-/- mice versus similarly treated WT mice. Allergic response was downregulated by re-introduction of recombinant Sema4A protein. However, the in vitro recall T cell response to OVA was not affected by Sema4A deficiency. These data provide a new insight into Sema4A biology and defines it as a critical regulator of Th2-driven lung pathophysiology.

Allergic asthma is characterized by exaggerated Th2 inflammation resulting from interaction between DC and T cells. Molecules acting in this interaction, regulating cell activation and differentiation are desirable therapeutic targets. Based on the previously published data and our results, we hypothesized that neuroimmune semaphorins play critical costimulatory roles in DC - T cell interaction, thereby influencing allergic lung inflammation. To test our hypothesis, we used Sema4A-/- and Sema4D-/- mice in the mouse model of OVA-induced allergic lung response. Our results have shown that both molecules play critical but opposite roles in disease severity. It was significantly potentiated by Sema4A deficiency, what included increased eosinophilic infiltration, AHR, local/systemic IL-13 levels, sera OVA-specific IgG1/ IgG2b/IgE levels, and decreased Treg numbers. Moreover, we defined that Sema4A expression on CD4+ T cells but not on DC was important for Th2 response regulation. In contrast, we found a decrease in lung inflammation and BAL Th2 cytokine levels in allergen-treated Sema4D-/- mice relative to WT mice. In addition, T cell proliferation in OVA323-339 - restimulated Sema4D-/- cell cultures was downregulated suggesting a costimulatory role of Sema4D for T cell activation. However, AHR was not affected by Sema4D deficiency suggesting its negligible role in airway physiology. These data define both molecules as important regulators of Th2-driven lung pathophysiology.

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