IFN-γ–producing self-reactive CD4+ T cells induce autoimmune adrenalitis in a mouse model of Addison’s disease
Arina Andreyeva, Juraj Michalik, Veronika Niederlova, Veronika Cimermanova, Ales Drobek, Radislav Sedlacek, Jan Prochazka, Juraj Labaj, Olha Fedosieieva, Waldemar Kanczkowski, Peter Draber, André Sulen, Ondrej Stepanek, Aleš Neuwirth
Arina Andreyeva, Juraj Michalik, Veronika Niederlova, Veronika Cimermanova, Ales Drobek, Radislav Sedlacek, Jan Prochazka, Juraj Labaj, Olha Fedosieieva, Waldemar Kanczkowski, Peter Draber, André Sulen, Ondrej Stepanek, Aleš Neuwirth
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Research Article Clinical Research Endocrinology

IFN-γ–producing self-reactive CD4+ T cells induce autoimmune adrenalitis in a mouse model of Addison’s disease

Abstract

Autoimmune Addison’s disease (AD) is a rare but life-threatening disorder caused by immune-mediated destruction of the adrenal cortex, and progress in therapy has been limited by insufficient mechanistic insight. Here, we establish a model of experimental autoimmune adrenalitis that recapitulates key features of AD and reveals sex-dependent differences in disease manifestation within the model. Immunization with peptides derived from the adrenal self-antigen CYP11A1 induces corticosterone insufficiency. We show that autoimmune adrenalitis is driven by IFN-γ produced by self-reactive CD4+ T cells, promoting granulomatous inflammation in the adrenal cortex. Together, these findings identify IFN-γ as a central effector of autoimmune adrenalitis and suggest that targeting the IFN-γ pathway may represent a potential therapeutic strategy for AD.

Authors

Arina Andreyeva, Juraj Michalik, Veronika Niederlova, Veronika Cimermanova, Ales Drobek, Radislav Sedlacek, Jan Prochazka, Juraj Labaj, Olha Fedosieieva, Waldemar Kanczkowski, Peter Draber, André Sulen, Ondrej Stepanek, Aleš Neuwirth

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Figure 5

CD4+ T cell–derived IFN-γ drives pathology in the adoptive EAA model.

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CD4+ T cell–derived IFN-γ drives pathology in the adoptive EAA model. (A...
(A) Adoptive EAA model design. CYP11A1-restimulated CD4+ T cells were transferred into Rag2−/− or Cd3e−/− recipients. Created with BioRender.com. (B) Serum corticosterone after ACTH stimulation in Rag2−/− (2 independent experiments; n = 9–12 mice/group) and Cd3e−/− (2 independent experiments; n = 7–8 mice/group) recipients 3 months after transfer. (C) Cortical granuloma frequency in Rag2−/− (2 independent experiments; n = 7–11 mice/group) and Cd3e−/− (2 independent experiments; n = 7–8 mice/group) recipients 3 months after transfer. (D) Representative H&E-stained adrenal sections from Rag2−/− recipients (2 independent experiments; n = 7–11 mice/group). Whole-organ sections (scale bar: 200 μm) and magnified views (scale bar: 100 μm). Adrenal borders, medulla, and granulomas are highlighted in yellow; asterisks indicate infiltrating leukocytes. (E) Quantification of adrenal CD4+ T cell infiltration in Rag2−/− recipients 3 months after transfer (2 independent experiments; n = 10–11 mice/group). (F–H) Comparison of CYP11A1 and CYP21 immunization. CD4+ T cells from pCYP11A1- or pCYP21-immunized B6 mice were restimulated with peptides and transferred into Cd3e−/− recipients (2 independent experiments; n = 5–7 mice/group; analysis at 3 months after transfer). (F) Quantification of CD4+ T cell infiltration. (G and H) Cortical granuloma frequency and serum corticosterone after ACTH stimulation. Cd3e−/− mice without transfer served as NT controls. (I–M) IFN-γ requirement in adoptive EAA. CD4+ T cells from Ifng+/+ or Ifng−/− donors were transferred into Rag2−/− recipients (2 independent experiments; n = 9–12 mice/group; analysis at 3 months after transfer). (I and J) Serum corticosterone after ACTH stimulation and cortical granuloma frequency. (K–M) CD4+ T cell infiltration and effector subset distribution. NT mice were not analyzed due to absence of T cells. (B, C, and E–M) Statistical significance was determined using the 2-tailed Mann-Whitney U test; (F–I) P values were adjusted using Bonferroni’s correction. P values are indicated. Bars show mean ± SEM; symbols represent mice.