Background/Purpose: Innate Lymphoid Cells (ILCs) are the innate counterparts to T cells and can be divided into three functionally distinct subpopulations: Group 1 (ILC1), Group 2 (ILC2), and Group 3 (ILC3). These tissue resident cells have been found in the synovium of rheumatoid arthritis (RA) patients, but their role in disease pathogenesis is largely unknown. ILC2s can serve as antigen presenting cells through expression of MHC-class II, suggesting they might contribute to disease progression by interacting with T cells in arthritic joints. We used the SKG mouse model, in which arthritis develops due to defective negative selection of autoreactive CD4⁺ T cells in the thymus leading to primarily Th17-driven autoimmune arthritis. By using this T cell dependent model, we aim to elucidate how ILC2 contribute to disease progression through their potential communication with T cells.

Methods: To induce SKG arthritis, arthritogenic CD4⁺ SKG T cells were transferred into T and B cell-deficient (Rag2^-/-) mice. The role of ILCs in SKG arthritis was evaluated by transferring CD4⁺ SKG T cells into ILC-deficient (Rag2^-/-IL2rg^–) mice. Additionally, ILC2s were sorted by flow cytometry, expanded in vitro, and adoptively co-transferred with CD4⁺ SKG T cells into ILC-deficient mice. Arthritis development was monitored by measuring ankle thickness. To investigate the effect of ILC2 on T cell proliferation and differentiation, sorted ILC2s were cultured with either total or naïve CD4⁺ SKG T cells. The phenotype of IL-33 stimulated ILC2s was analyzed in Rag2^-/- mice by flow cytometry. Statistical differences were determined using unpaired t-test.

Results: Phenotypic characterization identified ILC2s as the dominant ILC subpopulation in ankles of mice with SKG arthritis. The role of ILCs in SKG arthritis was supported by alleviated arthritis development in ILC-deficient mice after transfer of CD4⁺ SKG T cells (P=0.0023 vs control). Reconstitution of ILC-deficient mice with ILC2s aggravated arthritis development after transfer of CD4⁺ SKG T cells (P=0.0015 vs control), suggesting a disease-promoting role for ILC2 in SKG arthritis. Mechanistically, we found that IL-33 activated ILC2s promote T cell activation (41.2% ± 3.8 vs 3.3% ± 2.4; P= 0.0003) and proliferation (34.6 ± 7.5% vs 2.8 ± 1.9%; P=0.0007). Additionally, IL-33 activated ILC2s enhanced the differentiation of naïve SKG T cells into Th17 cells in vitro (25.2 ± 3.4% vs 19.3 ± 0.7%). Lastly, synovial ILC2s showed high MHC- class II expression in SKG arthritis. In vivo stimulation with RA-associated cytokine IL-33 increased MHC-class II expression in synovial ILC2s compared to controls. (38.3 ± 2% vs 3.2 ± 0.4%; P=0.0032).

Conclusion: ILC2s display a pathological role in arthritis progression by the aggravated disease profile in ILC-deficient mice after ILC2 transfer. Mechanistically we find that ILC2s enhance both SKG CD4+ T cell activation and proliferation as well as the differentiation of Th17 cells. The role of ILC2s as potent antigen presenting cells is further supported by their increased MHC-class II expression upon activation. These findings highlight ILC2s’ crucial role in promoting arthritis progression through direct interaction with arthritogenic T cells.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/group-2-innate-lymphoid-cells-promote-t-cell-activation-and-development-of-autoimmune-arthritis/