title: Pathogen Stimulation History Impacts Donor-Specific CD8(+) T Cell Susceptibility to Costimulation/Integrin Blockade-Based Therapy.
abstract: Recent studies have shown that the quantity of donor-reactive memory T cells is an important factor in determining the relative heterologous immunity barrier posed during transplantation. Here, we hypothesized that the quality of T cell memory also potently influences the response to costimulation blockade-based immunosuppression. Using a murine skin graft model of CD8(+) memory T cell-mediated costimulation blockade resistance, we elicited donor-reactive memory T cells using three distinct types of pathogen infections. Strikingly, we observed differential efficacy of a costimulation and integrin blockade regimen based on the type of pathogen used to elicit the donor-reactive memory T cell response. Intriguingly, the most immunosuppression-sensitive memory T cell populations were composed primarily of central memory cells that possessed greater recall potential, exhibited a less differentiated phenotype, and contained more multi-cytokine producers. These data, therefore, demonstrate that the memory T cell barrier is dependent on the specific type of pathogen infection via which the donor-reactive memory T cells are elicited, and suggest that the immune stimulation history of a given transplant patient may profoundly influence the relative barrier posed by heterologous immunity during transplantation.
authors.affiliation: Emory Transplant Center, Atlanta, GA.
authors.forename: I R
authors.initials: IR
authors.lastname: Badell
authors.affiliation: Emory Transplant Center, Atlanta, GA.
authors.forename: W H
authors.initials: WH
authors.lastname: Kitchens
authors.affiliation: Emory Transplant Center, Atlanta, GA.
authors.forename: M E
authors.initials: ME
authors.lastname: Wagener
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA.
authors.forename: A E
authors.initials: AE
authors.lastname: Lukacher
authors.affiliation: Emory Transplant Center, Atlanta, GA.
authors.forename: C P
authors.initials: CP
authors.lastname: Larsen
authors.affiliation: Emory Transplant Center, Atlanta, GA.
authors.forename: M L
authors.initials: ML
authors.lastname: Ford
mesh_terms: D000818:Animals; D001419:Bacteria / Q000472:pathogenicity*; D001424:Bacterial Infections / Q000209:etiology / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006084:Graft Rejection / Q000209:etiology / Q000628:therapy*; D006085:Graft Survival; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016023:Integrins / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012307:Risk Factors; D016038:Skin Transplantation; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D016023:Integrins
keywords: T cell biology; basic (laboratory) research/science; costimulation; fusion proteins and monoclonal antibodies: adhesion molecule specific; fusion proteins and monoclonal antibodies: costimulation molecule specific; immunobiology; immunosuppressant; immunosuppression/immune modulation; translational research/science