IFNAR signaling directly modulates T lymphocyte activity, resulting in milder experimental autoimmune encephalomyelitis development

Abstract

Although interferon-β is used as first-line therapy for multiple sclerosis, the cell type-specific activity of type I interferons in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis, remains obscure. In this study, we have elucidated the in vivo immunomodulatory role of type I interferon signaling in T cells during experimental autoimmune encephalomyelitis by use of a novel transgenic mouse, carrying a cd2-ifnar1 transgene on a interferon-α/β receptor 1 null genetic background, thus allowing expression of the interferon-α/β receptor 1 and hence, a functional type I interferon receptor exclusively on T cells. These transgenic mice exhibited milder experimental autoimmune encephalomyelitis with reduced T cell infiltration, demyelination, and axonal damage in the central nervous system. It is noteworthy that interferon-β administration in transgenic mice generated a more pronounced, protective effect against experimental autoimmune encephalomyelitis compared with untreated littermates. In vivo studies demonstrated that before experimental autoimmune encephalomyelitis onset, endogenous type I interferon receptor signaling in T cells led to impaired T-helper 17 responses, with a reduced fraction of CCR6(+) CD4(+) T cells in the periphery. At the acute phase, an increased proportion of interleukin-10- and interferon-γ-producing CD4(+) T cells was detected in the periphery of the transgenic mice, accompanied by up-regulation of the interferon-γ-induced gene Irgm1 in peripheral T cells. Together, these results reveal a hitherto unknown T cell-associated protective role of type I interferon in experimental autoimmune encephalomyelitis that may provide valuable clues for designing novel therapeutic strategies for multiple sclerosis.

Type I Interferons in the Pathogenesis of Tuberculosis: Molecular Drivers and Immunological Consequences

“…Thus, the overall impact of type I IFN signaling during mycobacterial infection may be a composite of differential effects on myeloid and lymphocyte cell functions. Mouse models that allow assessment of the impact of type I IFN signaling in specific cell subsets such as T cells ( 127 ) might prove valuable in dissecting the direct impact of type I IFNs on T cell functions during M. tuberculosis infection.…”

IFN-β differentially regulates the function of T cell subsets in MS and EAE

“…A study performed during the disease course pointed out that endogenous IFN-β reduces the frequency of CD4 + IL-17 + LN cells isolated on day 4 of EAE, but this effect was not observed on day 10 [58]. A recent study by our group, using ifnar1 Tecxl mice that express IFNAR selectively on T cells, showed that endogenous IFN-β acted directly on T cells in vivo ,reducing Th17responses in the periphery on day 10 of EAE, but this effect was reversed on day 17 [62]. In addition, silencing of irf7, a factor that mediates IFN-β production, in CD4 + T cells from MS patients, led to secretion of higher levels of IL-17A and IL-17F, suggesting that endogenous IFN-β suppressed Th17 responses [63].…”

“…Noteworthy, there are only two studies that reveal this specified action, using two different transgenic mouse models. Prinz et al generated ifnar1 fl/fl CD4 Cre mice that lack IFNAR on T cells [52], while our group reversely generated IFNAR1 Texcl mice that express IFNAR exclusively on T cells [62]. These two different approaches enriched our knowledge on the beneficial effect of IFN-β on T cells and its dependence on the cellular environment and disease stage.…”

“…Thorough investigation of the molecular mechanisms that underlie the beneficial effects of type I IFNs on each T cell subtype would be crucial for understanding the possibility of designing novel customized IFN-β-based therapies that selectively target and manipulate specific T cell subpopulation, thus possibly improving existing therapeutic interventions in MS. Expression of Th1 chemokines and their receptors on CD4 + T in the CNS [54] IFN-γ production by Th1 cells [53] ↓ ↓ ↑ Expression of T-bet and IFN-γ genes in the blood [43] CCR5 mRNA levels and its ligands on T cells [56] CCR5, IL-12Rβ2 and IFN-γ mRNA levels in PBMCs [57] Th17 ↓ ↓ ↓ IL-17 production by MOG-primed splenocytes [51] Frequency of CD4 + IL-17 + LN cells on day 4 of EAE [58] Frequency of CD4 + IL-17 + and CD4 + CCR6 + splenocytes and IL-17 production on day 10 of EAE [62] ↓ ↓ ↓ ↑ ↓ IL17 production by MOG-primed LN cells [28] IL17 mRNA levels in spleen and LN cells [37,64] Frequency of CD4 + IL-17 + cells in the brain [38] Production of IL-27 by DCs [38] Expression of Th17 chemokines and their receptors on CD4 + T cells in the CNS [54] ↓ IL-17A and IL-17F production by CD4 + T cells in PBMCs [63] ↓ ↓ ↓ ↓ Th17 cells differentiation in PBMCs [61,65] IL-17 mRNA and protein levels in PBMCs [66,67] Proportion of IL-17A + and IL-17F + CD4 + T cells in PBMCs [63] Expression of IL17C and IL23R genes in PBMCs [63] Tregs ↑ ↑ ↑ IL-10 production by splenocytes [28] IL-10 mRNA levels in PLP-specific T cells and IL-10 protein in PLP-primed LN cells [40] Treg proliferation [72] ↑ IL-10 and Foxp3 mRNA levels in serum and CSF [80] ↑ ↑ ↑ ↑ ↑ Treg function and proportion in peripheral blood [73] IL-10 mRNA and protein levels in PBMCs [40,82] IL-10 production by CD4 + T cells in PBMCs [65] IL-10 + cells in PBMCs [67,…”

A virus hosted in malaria-infected blood protects against T cell-mediated inflammatory diseases by impairing DC function in a type I IFN-dependent manner

“…Type I IFN are powerful signals that can modify the functionality of many cell types, including CD4 + T cells, which play a major role in the two diseases. For example, in EAE, IFN-I signaling in T cells can directly impair Th17 differentiation 71 . During blood stage malaria, CD4 + T cell-intrinsic IFN-I signaling induces T-bet and Blimp-1 expression, thereby promoting IL-10 + Tr1 responses in mice 72 as well as in humans 73 .…”