Abstract
CD4+ Th17 are heterogeneous in terms of cytokine production and capacity to initiate autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE). Here we demonstrate that experimental priming of encephalitogenic Th cells expressing RORγt and T-bet and producing IL-17A, IFN-γ and GM-CSF but not IL-10 (Th1/Th17), is dependent on the presence of pertussis toxin (PTX) at the time of immunization. PTX induces early production of IL-1β by CD11b+CCR2+Gr1+ myeloid cells, which are rapidly recruited to antigen-draining lymph nodes. PTX-induced generation of Th1/Th17 cells is impaired in IL-1β- and ASC-deficient mice and in mice in which myeloid cells are depleted or fail to migrate to lymph nodes and requires expression of IL-1R1 and MyD88 on both T cells and non-T cells. Collectively, these data shed light on the enigmatic function of PTX in EAE induction and suggest that inflammatory monocytes and microbial infection can influence differentiation of pathogenic Th1/Th17 cells in autoimmune diseases through production of IL-1β.
Highlights
Experimental autoimmune encephalomyelitis (EAE) is a wellestablished mouse model of multiple sclerosis (MS), a debilitating inflammatory demyelinating disease of the human central nervous system (CNS)
We report that pertussis toxin (PTX) promotes the priming of CD4 þ T cells producing IL-17A, IFN-g and granulocyte– macrophage colony-stimulating factor (GM-CSF), but not IL-10, by inducing the rapid recruitment of neutrophils and inflammatory monocytes in the antigen-draining lymph nodes and production of IL-1b, which is required for the expansion and differentiation of encephalitogenic Th1/Th17 cells in vivo
Consistent with the cytokine profile, T-bet and RORgt mRNAs were more abundantly expressed by 2D2 T cells from PTX-treated mice, whereas mRNAs for the arylhydrocarbon receptor (AhR) and IL-23R were expressed at comparable levels (Fig. 1d)
Summary
Experimental autoimmune encephalomyelitis (EAE) is a wellestablished mouse model of multiple sclerosis (MS), a debilitating inflammatory demyelinating disease of the human central nervous system (CNS). Studies established that interleukin (IL)-17-producing CD4 þ Th17 cells are required to induce EAE, as mice lacking RORgt, the Th17-specifying transcription factor, or IL-23, a Th17 growth and differentiation factor, are resistant to EAE induction[1,2,3]. It has been demonstrated that Th17 cells primed in vitro in the presence of transforming growth factor (TGF)-b1 and IL-6 and producing IL-17 and IL-10 are non-pathogenic when transferred in vivo in a passive model of EAE4,5. We report that PTX promotes the priming of CD4 þ T cells producing IL-17A, IFN-g and GM-CSF, but not IL-10 ( defined as Th1/Th17), by inducing the rapid recruitment of neutrophils and inflammatory monocytes in the antigen-draining lymph nodes and production of IL-1b, which is required for the expansion and differentiation of encephalitogenic Th1/Th17 cells in vivo
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