DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling
Akhilesh K. Singh, … , Troy R. Torgerson, Mohamed Oukka
Akhilesh K. Singh, … , Troy R. Torgerson, Mohamed Oukka
Published October 5, 2017
Citation Information: JCI Insight. 2017;2(19):e94275. https://doi.org/10.1172/jci.insight.94275.
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Research Article Immunology

DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling

Abstract

Foxp3+ Tregs possess potent immunosuppressive activity, which is critical for maintaining immune homeostasis and self-tolerance. Defects in Treg development or function result in inadvertent immune activation and autoimmunity. Despite recent advances in Treg biology, we still do not completely understand the molecular and cellular mechanisms governing the development and suppressive function of these cells. Here, we have demonstrated an essential role of the dedicator of cytokinesis 8 (DOCK8), guanine nucleotide exchange factors required for cytoskeleton rearrangement, cell migration, and immune cell survival in controlling Treg fitness and their function. Treg-specific DOCK8 deletion led to spontaneous multiorgan inflammation in mice due to uncontrolled T cell activation and production of proinflammatory cytokines. In addition, we show that DOCK8-deficient Tregs are defective in competitive fitness and in vivo suppressive function. Furthermore, DOCK8 controls IL-2 signaling, crucial for maintenance and competitive fitness of Tregs, via a STAT5-dependent manner. Our study provides potentially novel insights into the essential function of DOCK8 in Tregs and immune regulation, and it explains the autoimmune manifestations associated with DOCK8 deficiency.

Authors

Akhilesh K. Singh, Ahmet Eken, David Hagin, Khushbu Komal, Gauri Bhise, Azima Shaji, Tanvi Arkatkar, Shaun W. Jackson, Estelle Bettelli, Troy R. Torgerson, Mohamed Oukka

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Figure 1

Treg-specific deletion of DOCK8 causes autoimmunity.

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Treg-specific deletion of DOCK8 causes autoimmunity. (A and B) Flow plot...
(A and B) Flow plot and graph showing the frequency of Tregs in the spleen and LNs of WT and DOCK8-deficient mice. Data represents 2 experiments with 4 mice per group. (C and D) DOCK8-deficient T cells have intrinsic defect in IL-2 production in response to TCR stimulation. WT, DOCK8pri/pri, and CD4CreDOCK8fl/fl animal LN cells were stimulated with anti-CD3 and anti-CD28 for 24 hours, followed by 4-hour stimulation in the presence of PMA and Ionomycine and then intracellular cytokine staining for IL-2. Data represents 3 experiments with 3 mice per group. (E) Representative image of small mouse size, crusting of tail, and skin lesions that develop around ears of 8-week-old Foxp3CreDOCK8fl/fl mice compared with control (DOCK8fl/fl) mice. (F) Percent survival and (G) Representative images showing splenomegaly (first from left), lymphadenopathy (second from left), and inflammation in small intestine (third and fourth from left) and stomach (fifth from left) in 8-week-old Foxp3CreDOCK8fl/fl mice compared with control mice. (H) Representative section of lung stained with H&E depicting higher lymphocytic infiltration (pointed by arrow) in 8-week-old Foxp3CreDOCK8fl/fl mice in comparison with DOCK8fl/fl mice; ×20 magnification. (I) Elevated levels of anti–dsDNA IgM, IgG, and IgG2c (upper panel), and anti-Sm/RNP IgM, with a trend toward increased anti-Sm/RNP IgG and IgG2c Ab (lower panel) in Foxp3CreDOCK8fl/fl mice compared with age-matched controls. Data represent 5–12 mice per group. These data shown are the mean ± SD. Statistics were performed with Prism software by using t test (B and I) and 1-way ANOVA (D). *P < 0.05, **P < 0.01, ***P < 0.001.