Pertussis Toxin by Inducing IL-6 Promotes the Generation of IL-17-Producing CD4 Cells

Abstract

Compelling evidence has now demonstrated that IL-17-producing CD4 cells (Th17) are a major contributor to autoimmune pathogenesis, whereas CD4+CD25+ T regulatory cells (Treg) play a major role in suppression of autoimmunity. Differentiation of proinflammatory Th17 and immunosuppressive Treg from naive CD4 cells is reciprocally related and contingent upon the cytokine environment. We and others have reported that in vivo administration of pertussis toxin (PTx) reduces the number and function of mouse Treg. In this study, we have shown that supernatants from PTx-treated mouse splenic cells, which contained IL-6 and other proinflammatory cytokines, but not PTx itself, overcame the inhibition of proliferation seen in cocultures of Treg and CD4+CD25− T effector cells. This stimulatory effect could be mimicked by individual inflammatory cytokines such as IL-1β, IL-6, and TNF-α. The combination of these cytokines synergistically stimulated the proliferation of CD4+CD25− T effector cells despite the presence of Treg with a concomitant reduction in the percentage of FoxP3+ cells and generation of IL-17-expressing cells. PTx generated Th17 cells, while inhibiting the differentiation of FoxP+ cells, from naive CD4 cells when cocultured with bone marrow-derived dendritic cells from wild-type mice, but not from IL-6−/− mice. In vivo treatment with PTx induced IL-17-secreting cells in wild-type mice, but not in IL-6−/− mice. Thus, in addition to inhibiting the development of Treg, the immunoadjuvant activity of PTx can be attributable to the generation of IL-6-dependent IL-17-producing CD4 cells.

Experimental Autoimmune Encephalomyelitis (EAE) Induced by Antigen Pulsed Dendritic Cells in the C57BL/6 Mouse: Influence of Injection Route

“…Flow cytometric analysis of the bone marrow derived DCs in our study showed that in the presence of GM-CSF and IL-4 almost all generated DCs are of myeloid phenotype (CD11b + ) and despite of their subtype they could induce EAE in mice after three subcutaneous injections. Consistent with our results, Dittel et al reported that bone marrow derived DCs efficiently present an encephalitogenic peptide (MBP, AC [1][2][3][4][5][6][7][8][9][10][11] ) from myelin basic protein to antigen specific T cells and induced EAE when injected subcutaneously to B10.PL mice [11]. Indeed three distinct DCs populations are found to be present in the CNS during the clinical stage of EAE: myeloid DCs, plasmacytoid DCs and lymphoid DCs [3].…”

“…It was reported that pertussis toxin reduces the number of T regulatory cells as well as impairing the immunosuppressive function of these cells [8]. On the other hand, this toxin has the capacity to induce proinflammatory cytokines such as IL-6, thereby promoting the differentiation of Th17 cells which are a major contributor to the pathogenesis of autoimmune inflammatory mediated diseases [7].…”

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

“…1B). PTX is known to open the blood-brain barrier (26), inhibit Foxp3 expression on T cells (27), and enhance Th17 development in EAE (28). Our findings and a previous study by others (29) indicated that PTX is dispensable for the development of EAE in PD-1 −/− mice.…”

Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells

“…Thus, the impact on the reciprocal differentiation of Tregs and Th17 cells of pharmacological agents may represent an underlying basis of their immunoregulatory actions. Indeed, we reported that pertussis toxin (PTx), an immunological adjuvant commonly used to induce experimental autoimmune diseases, is able to promote the generation of Th17 cells while suppressing differentiation of Tregs (8,9). On the other hand, it was reported that retinoic acid, an immunosuppressive vitamin A metabolite, has the capacity to promote the generation of Tregs while suppressing differentiation of Th17 cells (10).…”