Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis.

BACKGROUND: Follicular regulatory T (TFR) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (TFH) cell-GC-antibody (Ab) response secondary to dysfunctional TFR cells is the root of an array of autoimmune disorders. The contribution of TFR cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear. METHODS: To determine the impact of dysregulated regulatory T cells (Tregs), TFR cells, and Ab responses on EAE, we compared the MOG-induced EAE in mice with a FoxP3-specific ablation of the transcription factor Blimp1 to control mice. In vitro co-culture assays were used to understand how Tregs and Ab regulate the activity of microglia and central nervous system (CNS)-infiltrating myeloid cells. RESULTS: Mice with a FoxP3-specific deletion of Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of Tregs into interleukin (IL)-17A/granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing effector T cells associated with increased TFH-Ab responses, more IgE deposition in the CNS, and inability to regulate CNS CD11b+ myeloid cells. Notably, serum IgE titers were positively correlated with EAE scores, and culture of CNS CD11b+ cells with sera from these EAE mice enhanced their activation, while transfer of Blimp1-deficient TFR cells promoted Ab production, activation of CNS CD11b+ cells, and EAE. CONCLUSIONS: Blimp1 is essential for the maintenance of TFR cells and Ab responses in EAE. Dysregulated TFR cells and Ab responses promote CNS autoimmunity.

Decreased Levels of STAT1 and Interferon-γ-Induced STAT1 Phosphorylation in Rheumatoid Arthritis CD4 and CD8 T Cells.

OBJECTIVE: We investigated whether a previously reported association of IFNGR expression with rheumatoid arthritis (RA) and its radiographic severity reflects differences in proximal interferon-γ (IFN-γ) signaling in T cells from patients with RA compared with healthy controls (HC). METHODS: Using phosphoflow cytometry, we compared IFN-γ-stimulated signal transducer and activator of transcription 1 (STAT1) activation in CD4+ and CD8+ T-cell populations from patients with RA and HC. RESULTS: Compared with controls, patients with RA had a higher proportion of CD4+ T cells, associated with expansion of the CD4+ effector memory subset. Several CD4+ T-cell types exhibited reduced IFN-γ-induced phosphoSTAT1Y701 (pSTAT1Y701 ) in patients with RA compared with HC. Engaging the T-cell receptor (TCR) complex on CD4+ T cells during IFN-γ stimulation abrogated the reduction in STAT1 activation in patients with RA but had no effect in HC. The phosphorylation of STAT1S727 was similar in CD4+ T cells from patients with RA and HC. In contrast to CD4+ T cells, IFN-γ-induced pSTAT1Y701 levels in CD8+ T cells were equivalent or higher in patients with RA compared with HC. Total STAT1 levels (phosphorylated + unphosphorylated) were lower in CD4+ and CD8+ T cells from patients with RA compared with HC. CONCLUSION: We report diminished IFN-γ-induced pSTAT1Y701 levels in CD4+ T cells in patients with RA, which were restored by TCR engagement. There were lower levels of total STAT1 in patients with RA compared with HC, but this likely does not explain diminished IFN-γ-induced pSTAT1Y701 levels in CD4+ T cells because activation in CD8+ T cells was higher or equivalent to that seen in HC. The enhanced IFNGR expression in patients with RA reported previously may reflect a compensatory mechanism to overcome deficiency in IFN-γ responsiveness.