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.

Interleukin-1 (IL-1) plays a crucial role in numerous inflammatory diseases via action on its only known signaling IL-1 receptor type 1 (IL-1R1). To investigate the role of IL-1 signaling in selected cell types, we generated a new mouse strain in which exon 5 of the Il1r1 gene is flanked by loxP sites. Crossing of these mice with CD4-Cre transgenic mice resulted in IL-1R1 loss of function specifically in T cells. These mice, termed IL-1R1ΔT, displayed normal development under steady state conditions. Importantly, isolated CD4 positive T cells retained their capacity to differentiate toward Th1 or Th17 cell lineages in vitro, and strongly proliferated in cultures supplemented with either anti-CD3/CD28 or Concanavalin A, but, as predicted, were completely unresponsive to IL-1β administration. Furthermore, IL-1R1ΔT mice were protected from gut inflammation in the anti-CD3 treatment model, due to dramatically reduced frequencies and absolute numbers of IL-17A and interferon (IFN)-γ producing cells. Taken together, our data shows the necessity of intact IL-1 signaling for survival and expansion of CD4 T cells that were developed in an otherwise IL-1 sufficient environment.

The function of NF-κB family members is controlled by multiple mechanisms including the transcriptional regulator Bcl-3, an atypical member of the IκB family. By using a murine model of conditional Bcl-3 overexpression specifically in T cells, we observed impairment in the development of Th2, Th1, and Th17 cells. High expression of Bcl-3 promoted CD4 T-cell survival, but at the same time suppressed proliferation in response to TCR stimulation, resulting in reduced CD4 T-cell expansion. As a consequence, T-cell-specific overexpression of Bcl-3 led to reduced inflammation in the small intestine of mice applied with anti-CD3 in a model of gut inflammation. Moreover, impaired Th17-cell development resulted in the resistance of Bcl-3 overexpressing mice to EAE, a mouse model of multiple sclerosis. Thus, we concluded that fine-tuning expression of Bcl-3 is needed for proper CD4 T-cell development and is required to sustain Th17-cell mediated pathology.

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.

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