Type I interferon signaling limits viral vector priming of CD8⁺ T cells during initiation of vitiligo and melanoma immunotherapy

Abstract

Vitiligo is an autoimmune skin disease in which epidermal melanocytes are targeted for destruction by CD8+ T cells specific for melanocyte/melanoma‐shared antigens. IFNγ is the central cytokine driving disease, but the role of type I IFN in vitiligo remains unclear. We investigated the functional role of type I IFN during vitiligo progression using two different mouse models: one induced with a vaccinia virus (VV) vaccine and one induced with dendritic cells to prime autoimmune T cells. Induction of vitiligo by VV in IFNaR‐deficient mice led to the development of severe vitiligo compared with wild‐type (WT) mice and was characterized by a significantly enhanced effector CD8+ T‐cell response. Severe vitiligo in this model was a result of VV persistence, because exacerbation of disease in IFNaR‐deficient mice was not observed when antigen‐pulsed dendritic cells were used to induce vitiligo instead of virus. Treatment of B16F10 melanoma‐inoculated mice with VV vaccine therapy also induced a significantly enhanced anti‐tumor response in IFNaR‐deficient mice compared with WT. These results not only help define the pathways responsible for vitiligo progression but also suggest that blockade of type I IFNs following administration of a VV vaccine may provide increased immunogenicity and efficacy for melanoma immunotherapy.

Keratinocyte-tethering modification for biologics enables location-precise treatment in mouse vitiligo

“…We recently generated an antigen-pulsed bone marrow-derived dendritic cell (BMDC)-based vitiligo mouse model and reported that disease is dependent on host IFNγ signaling (Riding et al, 2021). To induce vitiligo, irradiated Krt14-Kitl* mice receive co-transfer of Thy1.1 + transgenic PMEL CD8 + T cells and BMDCs loaded with the pmel cognate peptide.…”

“…BMDC-induced vitiligo was adapted from the previously described method (Riding et al, 2021). Bone marrow cells taken from the femurs and tibia of 8-16-week-old C57BL/6J mice after RBC lysis (MilliporeSigma) were cultured in BMDC differentiation medium [RPMI-1640 (MilliporeSigma , R8758), 10% FBS (MilliporeSigma), 100 U/ml penicillin-streptomycin, 20 ng/ml mouse GM-CSF (PeproTech), 10 ng/ml mouse IL-4 (PeproTech), 50 uM 2-mercaptoethanol] at 0.8×10 6 cells/ml.…”

“…Current treatments include topical calcineurin inhibitors, corticosteroids, and/or narrowband ultraviolet B phototherapy (Rodrigues et al, 2017), while targeted immunotherapy is of significant interest (Rosmarin et al, 2020). We have shown that mice harboring a conditional knockout of signal transducer and activator of transcription (STAT)-1 in keratinocytes blocked the recruitment of PMEL into the skin (Richmond et al, 2017a), however mice harboring type I interferon receptor knockout did not (Riding et al, 2021), indicating that keratinocytes promote T cell recruitment through IFNγ. Thus, preventing IFNγ signaling in keratinocytes may provide a targeted treatment option, a hypothesis consistent with the observed efficacy of topical ruxolitinib in vitiligo (Rosmarin et al, 2020).…”

Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin

“…Vitiligo was induced 38 by retro-orbital injection of one million autoreactive CD8 + T cells and one million of bone marrow-derived dendritic cells (BMDCs) into sublethally irradiated (500 rads 1 day before transfer) B6.Cg-Tg(KRT14-Kitl*)4XTG2Bjl/J hosts (The Jackson Laboratory; #009687). Autoreactive CD8 + T cells (PMELs) were purified from the spleen of PMEL TCR transgenic strain B6.Cg-Thy1a/Cy Tg(TcraTcrb)8Rest/J (The Jackson Laboratory; #005023) through negative selection on microbeads (Miltenyi Biotech; #130-095-236) according to the manufacturer’s instructions.…”

Translational Research in Vitiligo

“…One study reported type I IFN expression within lesions using CXCL9 and MxA as surrogate markers induced by IFNs, however these can be induced by IFNγ as well. Mouse studies do not support a role for type I IFNs in vitiligo, as IFNα receptor (IFNaR) knockout mice still develop vitiligo to the same extent ( 132 ). Thus, while IFNγ clearly plays an important role in vitiligo pathogenesis, it is still unclear whether other IFNs contribute to disease.…”