SH2 domain–containing adaptor protein B expressed in dendritic cells is involved in T-cell homeostasis by regulating dendritic cell–mediated Th2 immunity

Abstract

PurposeThe Src homology 2 domain–containing adaptor protein B (SHB) is widely expressed in immune cells and acts as an important regulator for hematopoietic cell function. SHB silencing induces Th2 immunity in mice. SHB is also involved in T-cell homeostasis in vivo. However, SHB has not yet been studied and addressed in association with dendritic cells (DCs).Materials and MethodsThe effects of SHB expression on the immunogenicity of DCs were assessed by Shb gene silencing in mouse bone marrow–derived DCs (BMDCs). After silencing, surface phenotype, cytokine expression profile, and T-cell stimulation capacity of BMDCs were examined. We investigated the signaling pathways involved in SHB expression during BMDC development. We also examined the immunogenicity of SHB-knockdown (SHBKD) BMDCs in a mouse atopic dermatitis model.ResultsSHB was steadily expressed in mouse splenic DCs and in in vitro–generated BMDCs in both immature and mature stages. SHB expression was contingent on activation of the mitogen- activated protein kinase/Foxa2 signaling pathway during DC development. SHBKD increased the expression of MHC class II and costimulatory molecules without affecting the cytokine expression of BMDCs. When co-cultured with T cells, SHBKD in BMDCs significantly induced CD4+ T-cell proliferation and the expression of Th2 cytokines, while the regulatory T cell (Treg) population was downregulated. In mouse atopic dermatitis model, mice inoculated with SHBKD DCs developed more severe symptoms of atopic dermatitis compared with mice injected with control DCs.ConclusionSHB expression in DCs plays an important role in T-cell homeostasis in vivo by regulating DC-mediated Th2 polarization.

Dendritic Cell-Mediated Th2 Immunity and Immune Disorders

“…Neither type of cDC2 subset induces differentiation or development of Th2 immunity but enhances Th2 responses by activating effector and memory T cells [3,47]. CD11b + DCs, however, are involved in the development of Th2 responses from naïve T cells in the regional LN upon activation and CCR7-dependent migration [11,49]. In addition, CXCR5 + DCs also play an important role in inducing Th2 immunity in intestinal nematode infection [50].…”

“…In another study, the negative effect of PU.1-expressing DCs in mediating Th2 responses was revealed to be due to the inhibition of GATA3 [59]. The mechanistic justification reveals PU.1 binds to a GATA3 promoter, which leads to the suppression of GATA3 expression, and high-level recruitment of the reported that SHB is highly expressed in mouse splenic DCs and in vitro-generated bone marrow-derived dendritic cells (BMDCs), and SHB-deficient BMDCs induce Th2 polarization in T/DC co-cultures [11]. When SHB-deficient DCs were inoculated into mice with atopic dermatitis, mice developed more severe disease symptoms [11].…”

“…The mechanistic justification reveals PU.1 binds to a GATA3 promoter, which leads to the suppression of GATA3 expression, and high-level recruitment of the reported that SHB is highly expressed in mouse splenic DCs and in vitro-generated bone marrow-derived dendritic cells (BMDCs), and SHB-deficient BMDCs induce Th2 polarization in T/DC co-cultures [11]. When SHB-deficient DCs were inoculated into mice with atopic dermatitis, mice developed more severe disease symptoms [11]. SHB expression in DCs was found to be regulated by p-38-MAPK signaling-mediated Foxa2 expression and activation [11].…”

“…When SHB-deficient DCs were inoculated into mice with atopic dermatitis, mice developed more severe disease symptoms [11]. SHB expression in DCs was found to be regulated by p-38-MAPK signaling-mediated Foxa2 expression and activation [11].…”

“…Murphy et al (2015) suggested that a Klf4-expressing DC subset is required for Th2 responses [10]. A recent study by Ahmed et al (2017) has shown that a DC subset expressing SH2 domain-containing adaptor protein B (SHB) ensures Th2 homeostasis by regulating DC-mediated Th2 immunity in atopic dermatitis (AD) mouse model [11]. These findings prompted us to investigate the role of these genes in DC-mediated Th2 immunity.…”