Distinct Roles of α7 nAChRs in Antigen-Presenting Cells and CD4+ T Cells in the Regulation of T Cell Differentiation

It is now apparent that immune cells express a functional cholinergic system and that alpha 7 nicotinic acetylcholine receptors (alpha 7 nAChRs) are involved in regulating T cell differentiation and the synthesis of antigen-specific antibodies and proinflammatory cytokines. Here, we investigated the specific function alpha 7 nAChRs on T cells and antigen presenting cells (APCs) by testing the effect of GTS-21, a selective alpha 7 nAChR agonist, on differentiation of CD4(+) T cells from ovalbumin (OVA)-specific TCR transgenic DO11.10 mice activated with OVA or OVA peptide323-339 (OVAp). GTS-21 suppressed OVA-induced antigen processing-dependent development of CD4(+) regulatory T cells (Tregs) and effector T cells (Th1, Th2, and Th17). By contrast, GTS-21 up-regulated OVAp-induced antigen processing-independent development of CD4(+) Tregs and effector T cells. GTS-21 also suppressed production of IL-2, IFN-g, IL-4, IL-17, and IL-6 during OVA-induced activation but, with the exception IL-2, enhanced their production during OVAp-induced activation. In addition, during antigen-nonspecific, APC-independent anti-CD3/ CD28 antibody-induced CD4(+) polyclonal T cell activation in the presence of respective polarizing cytokines, GTS-21 promoted development of all lineages, which indicates that GTS-21 also acts via a 7 nAChRs on T cells. These results suggest 1) that alpha 7 nAChRs on APCs suppress CD4(+) T cell activation by interfering with antigen presentation through inhibition of antigen processing; 2) that alpha 7 nAChRs on CD4(+) T cells up-regulate development of Tregs and effector T cells; and that alpha 7 nAChR agonists and antagonists could be potentially useful agents for immune response modulation and enhancement.