title: A combination of local inflammation and central memory T cells potentiates immunotherapy in the skin.
abstract: Adoptive T cell therapy uses the specificity of the adaptive immune system to target cancer and virally infected cells. Yet the mechanism and means by which to enhance T cell function are incompletely described, especially in the skin. In this study, we use a murine model of immunotherapy to optimize cell-mediated immunity in the skin. We show that in vitro-derived central but not effector memory-like T cells bring about rapid regression of skin-expressing cognate Ag as a transgene in keratinocytes. Local inflammation induced by the TLR7 receptor agonist imiquimod subtly yet reproducibly decreases time to skin graft rejection elicited by central but not effector memory T cells in an immunodeficient mouse model. Local CCL4, a chemokine liberated by TLR7 agonism, similarly enhances central memory T cell function. In this model, IL-2 facilitates the development in vivo of effector function from central memory but not effector memory T cells. In a model of T cell tolerogenesis, we further show that adoptively transferred central but not effector memory T cells can give rise to successful cutaneous immunity, which is dependent on a local inflammatory cue in the target tissue at the time of adoptive T cell transfer. Thus, adoptive T cell therapy efficacy can be enhanced if CD8(+) T cells with a central memory T cell phenotype are transferred, and IL-2 is present with contemporaneous local inflammation.
authors.affiliation: University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Fiorenza
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Kenna
authors.forename: Iain
authors.initials: I
authors.lastname: Comerford
authors.forename: Shaun
authors.initials: S
authors.lastname: McColl
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Steptoe
authors.forename: Graham R
authors.initials: GR
authors.lastname: Leggatt
authors.forename: Ian H
authors.initials: IH
authors.lastname: Frazer
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology / Q000637:transplantation; D007108:Immune Tolerance; D007111:Immunity, Cellular; D007156:Immunologic Memory / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000601:surgery / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012867:Skin / Q000166:cytology / Q000276:immunology* / Q000473:pathology*; D016038:Skin Transplantation / Q000276:immunology / Q000379:methods / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology* / Q000637:transplantation