IL-23 compensates for the absence of IL-1 signaling on CD4 T cells in EAE model

Abstract

Abstract Interleukin-1 (IL-1) is implicated in numerous pathologies, including multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE), which is believed to be a T cell-mediated disease. However, the lack of specific tools so far limited our understanding of the precise mechanisms of IL-1 action. We therefore generated a mouse strain allowing the conditional deletion of the only known signaling receptor for IL-1, IL-1 receptor type 1 (IL-1R1). Crossing of these mice to CMV-Cre or CD4-Cre transgenic mice resulted in IL-1R1 deletion globally or specifically in αβ T cells, respectively. When we induced EAE in these mice using a standard protocol, we found that Pertussis toxin administration leads to IL-1R1 dependent recruitment of myeloid cells to the draining lymph nodes and subsequent IL-1β production. This myeloid-derived IL-1β did not vitally contribute to the generation and plasticity of Th17 cells in general, but rather promoted expansion of a GM-CSF+ Th17 cell subset, thereby enhancing its encephalitogenic potential. Mice lacking IL-1R1 specifically in T cells, in contrast to complete IL-1R1 deficient animals, were not resistant to active EAE induction but rather developed a mild form of paralysis. CNS-infiltrating CD4 T cells included GM-CSF+ Th17 cells yet in reduced frequencies and numbers compared to wild type control animals. Moreover, the pathogenicity of IL-1R1 deficient T cells was fully restored by IL-23 polarization in vitro prior to transferring of sufficient numbers of these IL-17A+ cells into Rag1−/− recipient mice. Therefore, our data emphasize an important but dispensable function of IL-1 signaling in T cell mediated neuropathology.