Epidermal Cadm1 expression promotes autoimmune alopecia via enhanced T cell adhesion and cytotoxicity.
Autoimmune alopecia is characterized by an extensive epidermal T cell infiltrate that mediates hair follicle destruction. We have investigated the role of cell adhesion molecule 1 (Cadm1; Necl2) in this disease. Cadm1 is expressed by epidermal cells and mediates heterotypic adhesion to lymphocytes expressing class 1-restricted T cell-associated molecule (CRTAM). Using a murine autoimmune alopecia model, we observed an increase in early-activated cytotoxic (CD8-restricted, CRTAM-expressing) T cells, which preferentially associated with hair follicle keratinocytes expressing Cadm1. Coculture with Cadm1-transduced MHC-matched APCs stimulated alopecic lymph node cells to release IL-2 and IFN-γ. Overexpression of Cadm1 in cultured human keratinocytes did not promote cytokine secretion, but led to increased adhesion of alopecic cytotoxic T cells and enhanced T cell cytotoxicity in an MHC-independent manner. Epidermal overexpression of Cadm1 in transgenic mice led to increased autoimmune alopecia susceptibility relative to nontransgenic littermate controls. Our findings reveal that Cadm1 expression in the hair follicle plays a role in autoimmune alopecia.
Cancer Research UK Cambridge Research Institute, Cambridge CB2 0RE, United Kingdom.
Adam
A
Giangreco
Esther
E
Hoste
Yoshimi
Y
Takai
Ian
I
Rosewell
Fiona M
FM
Watt
D000505:Alopecia / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D000818:Animals; D001327:Autoimmune Diseases; D002448:Cell Adhesion; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000502:physiology*; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004198:Disease Susceptibility; D004817:Epidermis / Q000737:chemistry / Q000276:immunology*; D018859:Hair Follicle / Q000276:immunology / Q000473:pathology; D006801:Humans; D007136:Immunoglobulins / Q000502:physiology*; D015603:Keratinocytes; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology
C498598:Cadm1 protein, mouse; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D016207:Cytokines; D007136:Immunoglobulins