STAT1 signaling protects self-reactive T cells from control by innate cells during neuroinflammation
Carlos A. Arbelaez, Pushpalatha Palle, Jonathan Charaix, Estelle Bettelli
Carlos A. Arbelaez, Pushpalatha Palle, Jonathan Charaix, Estelle Bettelli
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Research Article

STAT1 signaling protects self-reactive T cells from control by innate cells during neuroinflammation

Abstract

The transcription factor STAT1 plays a critical role in modulating the differentiation of CD4+ T cells producing IL-17 and GM-CSF, which promote the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). The protective role of STAT1 in MS and EAE has been largely attributed to its ability to limit pathogenic Th cells and promote Tregs. Using mice with selective deletion of STAT1 in T cells (STAT1CD4-Cre), we identified a potentially novel mechanism by which STAT1 regulates neuroinflammation independently of Foxp3+ Tregs. STAT1-deficient effector T cells became the target of NK cell–mediated killing, limiting their capacity to induce EAE. STAT1-deficient T cells promoted their own killing by producing more IL-2 that, in return, activated NK cells. Elimination of NK cells restored EAE susceptibility in STAT1CD4-Cre mice. Therefore, our study suggests that the STAT1 pathway can be manipulated to limit autoreactive T cells during autoimmunity directed against the CNS.

Authors

Carlos A. Arbelaez, Pushpalatha Palle, Jonathan Charaix, Estelle Bettelli

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Figure 2

The resistance of STAT1CD4-Cre mice to EAE development is independent of Treg.

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The resistance of STAT1CD4-Cre mice to EAE development is independent of...
(A) Frequencies of Foxp3+ cells in MOG35–55–immunized WT control and STAT1CD4-Cre mice (n = 4 mice/group). Significance calculated with Mann-Whitney U test. (B) STAT1 expression in effector CD4+Foxp3– (Open histogram) and CD4+Foxp3+ (Gray-filled histogram) T cells from control (top) or STAT1fl/fl/Foxp3-IRES-Cre (STAT1FIC) (bottom) mice. (C) Frequencies of Foxp3+ Tregs in WT and STAT1FIC mice (n = 3–5 mice per group). Significance calculated with Mann-Whitney U test. (D) Clinical scores of WT control and STAT1FIC mice immunized with MOG35–55/CFA. Results are shown as mean ± SEM over time (n = 7–9 mice per group). Significance was calculated with 2-way ANOVA and Fisher’s LSD test. Data are representative of 2 experiments. (E) Summary of Foxp3+, IFN-γ+ (Th1), and IL-17+ (Th17) cells in the CNS of WT and STAT1FIC mice at the end of disease course on day 25 (n = 5–6 mice/group). Significance calculated with Mann-Whitney U test. (F) Percentage of CD4+CD25+Foxp3+ Tregs in the blood of WT and STAT1CD4-Cre mice treated with anti-CD25 or isotype control antibodies, 7 days after immunization with MOG35–55/CFA. Data are shown as mean ± SEM (n = 5 mice/group). Statistical significance was determined by the Mann-Whitney U test. (G) Clinical scores of WT control and STAT1CD4-Cre mice, treated with anti-CD25 and immunized with MOG35–55/CFA. Data are shown as mean clinical score ± SEM over time (n = 5 mice/group). Significance was calculated with 2-way ANOVA with Dunnett’s multiple-comparison test and indicated from day 13 between STAT1CD4-Cre and other groups (*P ≤ 0.05, **P ≤ 0.01, ****P ≤ 0.0001).