TLR7 stimulation augments T effector-mediated rejection of skin expressing neo-self antigen in keratinocytes.
Immunotherapy generally fails to induce tumour regression in spontaneously arising tumours. Failure is attributed to both tumour-related factors and an ineffective immune response. As a model of tumour immunotherapy, without the confounding effects of potential tumour-determined mechanisms of immune evasion, we studied the requirements for rejection of skin grafts expressing a neo-self antigen in somatic cells and not in antigen-presenting cells. When antigen expression was restricted to somatic cells, both CD4(+) and CD8(+) effector cells were required for graft rejection. Although freshly placed grafts were spontaneously rejected, healed grafts established under the cover of T cell depletion were not rejected even after T cell numbers recovered to a level where freshly placed grafts on the same animal were rejected, suggesting that healed skin grafts expressing a neo-self antigen only in somatic cells could not be rejected by primed recipients with functional effector T cells. Local TLR7 ligation induced inflammatory responses and rejection of healed grafts exposed to the TLR agonist but did not induce rejection of untreated healed grafts on the same animal. Thus, local pro-inflammatory signalling via TLR7 can promote effector T cell function against skin cells displaying their nominal antigen.
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D006084:Graft Rejection / Q000276:immunology*; D019382:Human Growth Hormone / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007167:Immunotherapy; D017403:In Situ Hybridization; D015603:Keratinocytes / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D016038:Skin Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology
D001324:Autoantigens; D015704:CD4 Antigens; D016827:CD8 Antigens; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D019382:Human Growth Hormone