Background/Purpose: Innate Lymphoid cells (ILCs) are innate counterparts to T-cells that, based on their functional phenotype, can be divided into three subpopulations called Group 1 (ILC1), Group 2 (ILC2) and Group 3 (ILC3). ILC subsets in autoimmune and chronic inflammatory diseases have been shown to display altered distribution and function, indicating subset-specific involvement. Although these tissue resident immune cells have been identified in the synovium of patients with rheumatoid arthritis (RA), their role in disease pathogenesis still remains largely unknown. SKG mice, which carry the Zap70W163C point mutation, develop autoimmune arthritis due to a defective negative selection of CD4+ T-cells in thymus. Here, we use the SKG mouse model to further assess the role of ILCs in arthritis development and find that ILCs have an important role in aggravating disease progression.

Methods: Arthritogenic CD4+ SKG T-cells were transferred to T and B cell deficient Rag2-knock out (Rag2-/-) mice to induce development of SKG arthritis. ILC subsets were evaluated in arthritic joints of mice with either spontaneous or mannan- induced SKG arthritis by flow cytometry. The role of ILCs in SKG arthritis was evaluated by transferring CD4+ SKG T-cells to ILC-deficient Rag2 and IL2rg double knockout (Rag2-/-IL2rg-) mice. Additionally, ILCs were isolated by flow cytometry, expanded in vitro and adoptively transferred in combination with CD4+ SKG T-cells into ILC-deficient (Rag2-/-IL2rg-) mice. Development of arthritis was monitored by clinical scoring. Mann-Whitney or un-paired T tests were used for statistical differences.

Results: Phenotypic characterization of ILC subsets in arthritic ankles revealed that ILC2 is the dominant synovial ILC population in joints of mice in both mannan-induced and spontaneous arthritis. ILC1 expanded in joint of mice during both mannan-induced and spontaneous arthritis. However, a synovial presence of ILC3 could only be observed in mice with mannan-induced arthritis. Surprisingly, there was no significant difference in severity between mannan-induced and spontaneous arthritis in Rag2^-/- mice after transfer of CD4⁺ SKG T cells. The role of ILC in SKG arthritis was supported by an alleviated arthritis development in ILC-deficient mice (P=0.041) after transfer with CD4+ SKG T cells. Finally, reconstitution of ILC-deficient mice with ILCs aggravated arthritis development after transfer with CD4+ SKG T cells (P=0.027).

Conclusion: Here we identify that ILC2 is the dominant ILC population in joints of mice with SKG arthritis. In addition, the aggravated development of arthritis in ILC-deficient mice after reconstitution of ILCs demonstrates the pathological effect of ILCs in SKG arthritis. Furthermore, the mannan-specific expansion of ILC3 in arthritic joints, suggest that synovial ILC3 are either directly or indirectly activated by inflammatory signals induced via the lectin pathway. Together, our results show that ILCs play a key role in promoting development of SKG arthritis and that different inflammatory triggers (e.g. mannan) induce unique synovial ILC distribution, which could result in specific synovial pathotypes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/innate-lymphoid-cells-enhance-development-of-cd4-t-cell-driven-autoimmune-arthritis/