Cytokine partnership to destruction

Researchers reporting in The Journal of Experimental Medicine have identified the mechanism behind a form of spontaneous autoimmune arthritis that occurs in mice with a mutation in the interleukin-6 (IL-6) receptor subunit gp130. Intriguingly, it turns out that signalling by this mutant IL-6 receptor in non-haematopoietic cells results in increased production of IL-7 by these cells. This, in turn, drives hyperproliferation of CD4⁺ T cells, contributing to arthritis.

To reach this conclusion, the authors first asked what cell population — haematopoietic or non-haematopoietic — might be responsible for disease in mice that have a single amino-acid change in gp130, termed gp130^F759/F759 mice. This mutation disrupts only one IL-6-receptor signalling pathway (the SH2 (SRC-homology 2)–MAPK (mitogen-activated protein kinase) pathway) and results in increased signalling through the STAT3 (signal transducer and activator of transcription 3) pathway. Surprisingly, lethally irradiated wild-type mice that received bone marrow from gp130^F759/F759 mice did not develop arthritis. By contrast, gp130^F759/F759 mice that received wild-type bone marrow did develop arthritis as normal, indicating that the disease was due to the mutation in non-haematopoietic cells. However, this did not preclude a role for haematopoietic cells in the disease process, as gp130^F759/F759 mice that lacked CD4⁺ T cells did not develop disease.

Next, on observing that gp130^F759/F759 mice had enlarged lymph nodes and spleens, the authors tested whether homeostatic proliferation of T cells might be involved, as has been described in other models of autoimmune disease. Indeed, after irradiation or neonatal thymectomy, homeostatic proliferation of CD4⁺ T cells was increased and more rapid in the mutant mice than in wild-type controls. Notably, thymectomized gp130^F759/F759 mice developed arthritis earlier than sham-operated gp130^F759/F759 mice, suggesting a role for increased homeostatic proliferation in the disease.

So, how does the non-haematopoietic-cell mutation in the IL-6 receptor induce CD4⁺ T-cell hyperproliferation? The authors showed that the expression of IL-7, which is known to be involved in T-cell proliferation, was markedly increased in gp130^F759/F759 non-haematopoietic cells. Moreover, treatment of these cells with IL-6, or other IL-6-family cytokines that also bind receptors that contain gp130, led to increased IL-7 production. Because the STAT3 pathway is functional in gp130^F759/F759 cells, the authors hypothesized that signalling through this pathway induced IL-7 production. Accordingly, conditional knockout of Stat3 in non-haematopoietic cells impaired IL-6-driven IL-7 production.

Finally, the important role for IL-7-mediated homeostatic proliferation of CD4⁺ T cells in the disease was confirmed by showing that in vivo depletion of IL-7 by treatment with specific antibody suppressed homeostatic proliferation and disease development in thymectomized gp130^F759/F759 mice.

This study provides the first evidence of a partnership between IL-6 and IL-7 in driving T-cell proliferation. Whether such a mechanism occurs in the joints of patients with rheumatoid arthritis, which have been shown to contain increased amounts of IL-6, will be the subject of future studies.