IL ‐1 signaling is critical for expansion but not generation of autoreactive GM ‐ CSF ⁺ Th17 cells

Abstract

Interleukin-1 (IL-1) is implicated in numerous pathologies, including multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). However, the exact mechanism by which IL-1 is involved in the generation of pathogenic T cells and in disease development remains largely unknown. We found that following EAE induction, pertussis toxin administration leads to IL-1 receptor type 1 (IL-1R1)-dependent IL-1b expression by myeloid cells in the draining lymph nodes. This myeloid-derived IL-1b did not vitally contribute to the generation and plasticity of Th17 cells, but rather promoted the expansion of a GM-CSF + Th17 cell subset, thereby enhancing its encephalitogenic potential. Lack of expansion of GM-CSF-producing Th17 cells led to ameliorated disease in mice deficient for IL-1R1 specifically in T cells. Importantly, pathogenicity of IL-1R1-deficient T cells was fully restored by IL-23 polarization and expansion in vitro. Therefore, our data demonstrate that IL-1 functions as a mitogenic mediator of encephalitogenic Th17 cells rather than qualitative inducer of their generation.

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

“…Schiffenbauer et al first reported that IL-1R-deficient mice (on a mixed genetic background) were resistant to active EAE induction (28). 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).…”

“…Because IL-1R1 knockout mice resisted active EAE induction but were susceptible to EAE when they served as recipients for adoptively transferred IL-1R-sufficient MOG-specific T H 17 cells, Sutton et al reasoned that T H 17 cells themselves must be critical responders to IL-1β (29). Furthermore, Rag1 -deficient mice reconstituted with IL-1R1-deficient CD4 + T cells (77) and mice with T cell-specific ablation of IL-1R1 ( Il1r1 fl/fl Cd4 -Cre) developed milder clinical EAE after immunization (34), confirming a T H cell-intrinsic role for IL-1 responsiveness. Ghoreschi et al demonstrated that IL-1β in combination with IL-6 and IL-23 was critically required for the generation of pathogenic T H 17 cells using a system of adoptively transferred in vitro polarized MOG-specific 2D2 TCR transgenic T H cells (78).…”

“…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). …”

“…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. We and the laboratories of Sallusto and Waisman explicitly showed a requirement for PTX to yield IL-1β production from this DLN cell population, by comparing MOG 35-55 /CFA immunizations with and without PTX (32, 34, 36). While the details of how PTX induces DLN cells to generate IL-1β are not clear, Dumas et al had previously shown that intraperitoneal PTX alone was sufficient to induce IL-1β production by macrophages and neutrophils in the peritoneum within a few hours after injection (63).…”

“…After EAE induction, IL-17A-producing as well as IFN-γ- and GM-CSF-producing CD4 + T cells in the DLN show higher IL-1R1 expression compared to Foxp3 + regulatory T cells (34). Because IL-1R1 knockout mice resisted active EAE induction but were susceptible to EAE when they served as recipients for adoptively transferred IL-1R-sufficient MOG-specific T H 17 cells, Sutton et al reasoned that T H 17 cells themselves must be critical responders to IL-1β (29).…”