Research ArticleImmunology

ROCK2 signaling is required to induce a subset of T follicular helper cells through opposing effects on STATs in autoimmune settings

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Sci. Signal.  19 Jul 2016:
Vol. 9, Issue 437, pp. ra73
DOI: 10.1126/scisignal.aad8953

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Preventing T cells from promoting autoimmunity

T follicular helper (TFH) cells are a subset of T cells that provide help to B cells to produce antibodies. Dysregulation of TFH cells is associated with autoimmune diseases, such as systemic lupus erythematosus (SLE). With T cells in culture, Weiss et al. found that KD025, a pharmacological inhibitor of the kinase ROCK2, blocked the generation and function of human TFH cells in response to the activation of peripheral blood T cells from active SLE patients. Unlike a general immunosuppressant, KD025 reduced TFH generation and ameliorated disease severity in a mouse model of SLE without interfering with other immune cells. Together, these data suggest that ROCK2 may be a therapeutic target in the treatment of autoimmune diseases.

Abstract

Rho-associated kinase 2 (ROCK2) determines the balance between human T helper 17 (TH17) cells and regulatory T (Treg) cells. We investigated its role in the generation of T follicular helper (TFH) cells, which help to generate antibody-producing B cells under normal and autoimmune conditions. Inhibiting ROCK2 in normal human T cells or peripheral blood mononuclear cells from patients with active systemic lupus erythematosus (SLE) decreased the number and function of TFH cells induced by activation ex vivo. Moreover, inhibition of ROCK2 activity decreased the abundance of the transcriptional regulator Bcl6 (B cell lymphoma 6) and increased that of Blimp1 by reducing the binding of signal transducer and activator of transcription 3 (STAT3) and increasing that of STAT5 to the promoters of the genes Bcl6 and PRDM1, respectively. In the MRL/lpr murine model of SLE, oral administration of the selective ROCK2 inhibitor KD025 resulted in a twofold reduction in the numbers of TFH cells and antibody-producing plasma cells in the spleen, as well as a decrease in the size of splenic germinal centers, which are the sites of interaction between TFH cells and B cells. KD025-treated mice showed a substantial improvement in both histological and clinical scores compared to those of untreated mice and had reduced amounts of Bcl6 and phosphorylated STAT3, as well as increased STAT5 phosphorylation. Together, these data suggest that ROCK2 signaling plays a critical role in controlling the development of TFH cells induced by autoimmune conditions through reciprocal regulation of STAT3 and STAT5 activation.

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