The Role of PD-L1 on Langerhans Cells in the Regulation of Psoriasis

      Langerhans cells (LCs) are skin-resident cells with potent antigen-presenting cell capabilities, which reportedly play some roles in the development of psoriasis, an inflammatory skin disease mediated by IL-17A‒producing cells, T helper 17 cells, and TCR-γδlow T cells. LCs in psoriatic skin lesions but not in normal skin express PD-L1, which binds to PD-1, an immune checkpoint molecule, to negatively regulate immune reactions. The aim of this study is to elucidate the regulatory role of LCs through the PD-1/PD-L1 axis in a murine model of imiquimod-induced psoriasis-like dermatitis. Imiquimod application on wild-type C57BL/6J mice induced PD-L1 expression on LCs both in the ear skin and skin-draining lymph nodes. To further identify the functional role of PD-L1 expressed on LCs, we generated conditional knockout mice lacking PD-L1 expression on LCs (Pd-l1-cKO mice). Pd-l1-cKO mice presented significantly more severe imiquimod-induced psoriasis-like dermatitis than their control littermates. Flow cytometric analysis showed that the frequency of activated IL-17A‒producing γδlow T cells was increased in the ear skin samples, and IL-17A production by CCR6+ migrating γδlow T cells increased in the skin-draining lymph nodes in imiquimod-applied Pd-l1-cKO mice than in control littermates. Collectively, LCs disrupt the exacerbation of psoriasis through PD-L1.


      Ctrl (control), DC (dendritic cell), dLN (draining lymph node), IMQ (imiquimod), LC (Langerhans cell), Th (T helper)
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        • Bonigen J.
        • Raynaud-Donzel C.
        • Hureaux J.
        • Kramkimel N.
        • Blom A.
        • Jeudy G.
        • et al.
        Anti-PD1-induced psoriasis: a study of 21 patients.
        J Eur Acad Dermatol Venereol. 2017; 31: e254-e257
        • Chan J.R.
        • Blumenschein W.
        • Murphy E.
        • Diveu C.
        • Wiekowski M.
        • Abbondanzo S.
        • et al.
        IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis.
        J Exp Med. 2006; 203: 2577-2587
        • Clark R.A.
        • Kupper T.S.
        Misbehaving macrophages in the pathogenesis of psoriasis.
        J Clin Invest. 2006; 116: 2084-2087
        • Dong H.
        • Zhu G.
        • Tamada K.
        • Chen L.
        B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion.
        Nat Med. 1999; 5: 1365-1369
        • Eyerich S.
        • Zielinski C.E.
        Defining Th-cell subsets in a classical and tissue-specific manner: examples from the skin.
        Eur J Immunol. 2014; 44: 3475-3483
        • Fuentes-Duculan J.
        • Suárez-Fariñas M.
        • Zaba L.C.
        • Nograles K.E.
        • Pierson K.C.
        • Mitsui H.
        • et al.
        A subpopulation of CD163-positive macrophages is classically activated in psoriasis.
        J Invest Dermatol. 2010; 130: 2412-2422
        • Gilliet M.
        • Conrad C.
        • Geiges M.
        • Cozzio A.
        • Thürlimann W.
        • Burg G.
        • et al.
        Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors.
        Arch Dermatol. 2004; 140: 1490-1495
        • Gomez de Agüero M.
        • Vocanson M.
        • Hacini-Rachinel F.
        • Taillardet M.
        • Sparwasser T.
        • Kissenpfennig A.
        • et al.
        Langerhans cells protect from allergic contact dermatitis in mice by tolerizing CD8(+) T cells and activating Foxp3(+) regulatory T cells.
        J Clin Invest. 2012; 122: 1700-1711
        • Hawkes J.E.
        • Yan B.Y.
        • Chan T.C.
        • Krueger J.G.
        Discovery of the IL-23/IL-17 signaling pathway and the treatment of psoriasis.
        J Immunol. 2018; 201: 1605-1613
        • Hitzler M.
        • Majdic O.
        • Heine G.
        • Worm M.
        • Ebert G.
        • Luch A.
        • et al.
        Human Langerhans cells control Th cells via programmed death-ligand 1 in response to bacterial stimuli and nickel-induced contact allergy.
        PLoS One. 2012; 7e46776
        • Igyártó B.Z.
        • Haley K.
        • Ortner D.
        • Bobr A.
        • Gerami-Nejad M.
        • Edelson B.T.
        • et al.
        Skin-resident murine dendritic cell subsets promote distinct and opposing antigen-specific T helper cell responses.
        Immunity. 2011; 35: 260-272
        • Iijima S.
        • Miyazaki K.
        • Sato S.
        • Kodama T.
        A case of de novo psoriasis induced by atezolizumab in a patient with advanced lung cancer.
        J cutan Immunol All. 2019; 2: 178-179
        • Imai Y.
        • Ayithan N.
        • Wu X.
        • Yuan Y.
        • Wang L.
        • Hwang S.T.
        Cutting edge: PD-1 regulates imiquimod-induced psoriasiform dermatitis through inhibition of IL-17A expression by innate γδ-low T cells.
        J Immunol. 2015; 195: 421-425
        • Kaplan D.H.
        • Li M.O.
        • Jenison M.C.
        • Shlomchik W.D.
        • Flavell R.A.
        • Shlomchik M.J.
        Autocrine/paracrine TGFbeta1 is required for the development of epidermal Langerhans cells.
        J Exp Med. 2007; 204: 2545-2552
        • Kautz-Neu K.
        • Noordegraaf M.
        • Dinges S.
        • Bennett C.L.
        • John D.
        • Clausen B.E.
        • et al.
        Langerhans cells are negative regulators of the anti-Leishmania response.
        J Exp Med. 2011; 208: 885-891
        • Kubo A.
        • Nagao K.
        • Yokouchi M.
        • Sasaki H.
        • Amagai M.
        External antigen uptake by Langerhans cells with reorganization of epidermal tight junction barriers.
        J Exp Med. 2009; 206: 2937-2946
        • Kubota N.
        • Saito A.
        • Tanaka R.
        • Nakamura Y.
        • Watanabe R.
        • Fujisawa Y.
        • et al.
        Langerhans cells suppress CD8+ T cells in situ during mucocutaneous acute graft-versus host disease.
        J Invest Dermatol. 2021; 141: 1177-1187.e3
        • Langrish C.L.
        • Chen Y.
        • Blumenschein W.M.
        • Mattson J.
        • Basham B.
        • Sedgwick J.D.
        • et al.
        IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
        J Exp Med. 2005; 201: 233-240
        • Martini E.
        • Wikén M.
        • Cheuk S.
        • Gallais Sérézal I.
        • Baharom F.
        • Ståhle M.
        • et al.
        Dynamic changes in resident and infiltrating epidermal dendritic cells in active and resolved psoriasis.
        J Invest Dermatol. 2017; 137: 865-873
        • Matsumura N.
        • Ohtsuka M.
        • Kikuchi N.
        • Yamamoto T.
        Exacerbation of psoriasis during nivolumab therapy for metastatic melanoma.
        Acta Derm Venereol. 2016; 96: 259-260
        • Ohtsuka M.
        • Miura T.
        • Mori T.
        • Ishikawa M.
        • Yamamoto T.
        Occurrence of psoriasiform eruption during nivolumab therapy for primary oral mucosal melanoma.
        JAMA Dermatol. 2015; 151: 797-799
        • Rajan N.
        • Langtry J.A.
        Generalized exacerbation of psoriasis associated with imiquimod cream treatment of superficial basal cell carcinomas.
        Clin Exp Dermatol. 2006; 31: 140-141
        • Rodig N.
        • Ryan T.
        • Allen J.A.
        • Pang H.
        • Grabie N.
        • Chernova T.
        • et al.
        Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis.
        Eur J Immunol. 2003; 33: 3117-3126
        • Seneschal J.
        • Clark R.A.
        • Gehad A.
        • Baecher-Allan C.M.
        • Kupper T.S.
        Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells.
        Immunity. 2012; 36: 873-884
        • Tanaka R.
        • Ichimura Y.
        • Kubota N.
        • Saito A.
        • Nakamura Y.
        • Ishitsuka Y.
        • et al.
        Activation of CD8 T cells accelerates anti-PD-1 antibody-induced psoriasis-like dermatitis through IL-6.
        Commun Biol. 2020; 3: 571
        • Tanaka R.
        • Ichimura Y.
        • Kubota N.
        • Saito A.
        • Nakamura Y.
        • Ishitsuka Y.
        • et al.
        Differential involvement of programmed cell death ligands in skin immune responses.
        J Invest Dermatol. 2022; 142: 145-154.e8
        • Tanaka R.
        • Okiyama N.
        • Okune M.
        • Ishitsuka Y.
        • Watanabe R.
        • Furuta J.
        • et al.
        Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tumor necrosis factor-alpha is a biomarker of nivolumab recativity.
        J Dermatol Sci. 2017; 86: 71-73
        • Tsushima F.
        • Iwai H.
        • Otsuki N.
        • Abe M.
        • Hirose S.
        • Yamazaki T.
        • et al.
        Preferential contribution of B7-H1 to programmed death-1-mediated regulation of hapten-specific allergic inflammatory responses.
        Eur J Immunol. 2003; 33: 2773-2782
        • van der Fits L.
        • Mourits S.
        • Voerman J.S.
        • Kant M.
        • Boon L.
        • Laman J.D.
        • et al.
        Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.
        J Immunol. 2009; 182: 5836-5845
        • Xiao C.
        • Zhu Z.
        • Sun S.
        • Gao J.
        • Fu M.
        • Liu Y.
        • et al.
        Activation of Langerhans cells promotes the inflammation in imiquimod-induced psoriasis-like dermatitis.
        J Dermatol Sci. 2017; 85: 170-177
        • Yoshiki R.
        • Kabashima K.
        • Honda T.
        • Nakamizo S.
        • Sawada Y.
        • Sugita K.
        • et al.
        IL-23 from Langerhans cells is required for the development of imiquimod-induced psoriasis-like dermatitis by induction of IL-17A-producing γδT cells.
        J Invest Dermatol. 2014; 134: 1912-1921
        • Zou W.
        • Wolchok J.D.
        • Chen L.
        PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations.
        Sci Transl Med. 2016; 8: 328rv4