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 6

NK cells selectively target STAT1-deficient CD4+ T cells for elimination and suppress EAE.

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NK cells selectively target STAT1-deficient CD4+ T cells for elimination...
(A and B) Congenically marked CD4+ T cells from 2D2 (CD45.2+) and STAT1CD4-Cre/2D2 (CD45.1+CD45.2+) were cotransferred into RAGKO and RAGKOIL-15KO mice at a 1:1 ratio, followed by immunization with MOG35–55/CFA. Six days after transfer, the draining lymph nodes were harvested. Frequencies (A) and quantification expressed as the percentage of total CD4+ T cells (B) of WT 2D2 (CD45.2+) and STAT1-deficient 2D2 (CD45.1+CD45.2+) donor CD4+ T cells, assessed by flow cytometry. Significance was calculated with 2-way ANOVA with Sidak’s multiple-comparison test (n = 3–4 mice per group). (C) CD4+ T cells from 2D2 and STAT1CD4-Cre/2D2 were transferred into RAGKO and RAGKOIL-15KO mice 1 day before immunization with MOG35-55/CFA — and treatment with pertussis toxin at the time of immunization — and 2 days later. Clinical scores of mice are shown. Results are shown as mean ± SEM over time. Significance was calculated with 2-way ANOVA with Dunnett’s test (n = 7–8 mice/group). (D and E) Congenically marked naive CD4+ T cells from 2D2 (CD45.2+) and STAT1CD4-Cre/2D2 (CD45.1+CD45.2+) were cotransferred into anti-NK1.1 mAb– or isotype control–treated RAGKO mice at a 1:1 ratio, followed by immunization with MOG35–55/CFA. Six days after transfer, the draining lymph nodes were harvested. Frequencies (D) and quantification (E) of WT (CD45.2+) and STAT1-deficient (CD45.1+CD45.2+) donor CD4+ T cells, assessed by flow cytometry. Significance was calculated with 2-way ANOVA with Sidak’s multiple-comparison test. Data are representative of 2 experiments with n = 5 mice/group. (F) Effects of anti-NK1.1 mAb treatment on the development and progression of EAE in control and STAT1CD4-Cre mice. Results are shown as mean ± SEM over time. Significance was calculated with 2-way ANOVA with Fisher’s LSD test (n = 10–12 mice per group). Data are representative of 2 experiments (*P ≤ 0.05, **P ≤ 0.01, #P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001).