Experimental priming of encephalitogenic Th1/Th17 cells requires pertussis toxin-driven IL-1β production by myeloid cells

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.

New Insights into the Role of IL-1β in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

“…These authors also found that transmigration through the blood-spinal cord barrier triggered pro-IL-1β expression by neutrophils, and that at day seven after EAE induction, IL-1β-producing neutrophils were found in the blood. We and others also found IL-1β-producing myeloid cells in peripheral lymphoid organs at days five through eight following EAE induction (31, 32, 36, 62). These reports collectively identified a population of CD11b + Ly6C mid-hi MHC II lo-hi monocyte-derived DC/macrophages (moDCs/Macs) as the main source of IL-1β in draining lymph nodes (DLNs), and showed that these cells increase dramatically following MOG 35-55 /CFA immunization given with PTX coadjuvant.…”

“…For this reason, the remainder of this review will focus on IL-1β, although whether IL-1α plays any role in MS remains an open question. Consistent with a critical requirement for IL-1β for EAE susceptibility, mice deficient in the inflammasome components NLRP3 (37–41), ASC (36, 39, 42), caspase 1 (42, 43), and caspase 11 (44) were also at least partially resistant to EAE, as were mice treated with inhibitors of NLRP3 (45, 46) or caspase 1 (47). It is worth noting that in some reports (40–42), mice immunized with larger amounts of heat-killed Mycobacterium tuberculosis ( Mtb ) (usually greater than 300 micrograms per mouse) as part of the MOG 35-55 /CFA emulsion developed an NLPR3- and ASC-independent form of aggressive EAE.…”

“…Their results have been confirmed by several other groups using IL-1R-deficient mice on the C57BL/6 background (29–34), although the degree to which these mice were protected from clinical disease was somewhat variable. Despite one report to the contrary (35), IL-1β appears to be the critical mediator of EAE, rather than IL-1α, as IL-1β-deficient mice were seen to resist EAE by two groups (33, 36), while IL-1α-deficient mice remained susceptible (33, 35). For this reason, the remainder of this review will focus on IL-1β, although whether IL-1α plays any role in MS remains an open question.…”

“…It is worth noting that in some reports (40–42), mice immunized with larger amounts of heat-killed Mycobacterium tuberculosis ( Mtb ) (usually greater than 300 micrograms per mouse) as part of the MOG 35-55 /CFA emulsion developed an NLPR3- and ASC-independent form of aggressive EAE. However, this form of EAE still appears to be IL-1β- and IL-1R-dependent, given that the experiments in IL-1β- and IL-1R-deficient mice which demonstrated EAE resistance were typically performed with large amounts of heat-killed Mtb (29–34, 36). …”

Pertussis Toxin Exploits Host Cell Signaling Pathways Induced by Meningitis-Causing E. coli K1-RS218 and Enhances Adherence of Monocytic THP-1 Cells to Human Cerebral Endothelial Cells

“…the development of encephalitogenic T cells [53]. In future studies it might also be interesting to investigate the putative effects of PTx on the c-Jun- N -terminal kinase (JNK) pathway.…”