“That’s not helping”–T follicular helper cells drive skin fibrosis

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Science Immunology  06 Apr 2018:
Vol. 3, Issue 22, eaat6417
DOI: 10.1126/sciimmunol.aat6417


T follicular helper–like cells and IL-21 are drivers of skin fibrosis in systemic sclerosis.

Systemic sclerosis (SSc) is a difficult to control, often devastating inflammatory disease that leads to widespread fibrotic scarring. The immune culprit that initiates this inappropriate scarring remains a mystery, but there are some clues. The inducible costimulatory molecule (ICOS), a B7/CD28 superfamily member up-regulated on activated T helper cells and expressed at highest levels by T follicular helper cells (TFH), is known to be increased in SSc patients, as is interleukin-21 (IL-21). ICOS+ TFH are increased in patients with lupus and rheumatoid arthritis where they correlate with disease activity, but these cells have not been associated with the fibrosis of SSc. The authors provide evidence for the additional misbehavior of these cells in SSc, showing that ICOS+ TFH-like cells are increased in sclerotic SSc skin lesions and correlate with disease activity. These cells also preceded and accompanied fibrosis in the skin of sclerodermatous GVHD (GVHD-SSc) mice, putting them in the right place at the right time to be drivers of fibrosis. Removal of ICOS+ cells with a depleting antibody blocked the expansion of TFH in skin, reduced cytokine production by ICOS+ cells (interferon γ and IL-21), and ameliorated fibrosis. IL-21 production was completely abrogated by this treatment. When the authors specifically neutralized IL-21, fibrosis was ameliorated as well. The authors provided a link between TFH and the myofibroblasts that drive skin fibrosis. Coculture of fibroblasts in vitro differentiated TFH led to up-regulation of α-smooth muscle actin, suggesting TFH can drive myofibroblast differentiation. IL-21 treatment of fibroblasts induced production of matrix metalloproteinase 12 and up-regulated the IL-21 receptor. Taken together, these findings suggest that ICOS+ TFH cells invading the skin of SSc patients may initiate a fibrotic inflammatory program that then takes on a life of its own, driving fibroblasts to differentiate into myofibroblasts and leading to progressive tissue fibrosis and destruction. If so, depletion or inhibition of TFH could lead to novel therapies for fibrotic disorders.

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