Limiting the amount and duration of antigen exposure during priming increases memory T cell requirement for costimulation during recall.
Donor-reactive memory T cells (Tmem) can play an important role in mediating graft rejection after transplantation. Transplant recipients acquire donor-reactive Tmem not only through prior sensitization with alloantigens but also through previous exposure to environmental pathogens that are cross-reactive with allogeneic peptide-MHC complexes. Current dogma suggests that most, if not all, Tmem responses are independent of the requirement for CD28 and/or CD154/CD40-mediated costimulation to mount a recall response. However, heterogeneity among Tmem is increasingly being appreciated, and one important factor known to impact the function and phenotype of Ag-specific T cell responses is the amount/duration of Ag exposure. Importantly, the impact of Ag exposure on development of costimulation independence is currently unknown. In this study, we interrogated the effect of decreased Ag amount/duration during priming on the ability of donor-reactive Tmem to mediate costimulation blockade-resistant rejection during a recall response after transplantation in a murine model. Recipients possessing donor-reactive Tmem responses that were generated under conditions of reduced Ag exposure exhibited similar frequencies of Ag-specific T cells at day 30 postinfection, but, strikingly, failed to mediate costimulation blockade-resistant rejection after challenge with an OVA-expressing skin graft. Thus, these data demonstrate the amount/duration of Ag exposure is a critical factor in determining Tmem's relative requirement for costimulation during the recall response after transplantation.
Department of Surgery and Emory Transplant Center, Emory University, Atlanta, GA 30322, USA.
Tamara L
TL
Floyd
Brent H
BH
Koehn
William H
WH
Kitchens
Jennifer M
JM
Robertson
Jennifer A
JA
Cheeseman
Linda
L
Stempora
Christian P
CP
Larsen
Mandy L
ML
Ford
D000667:Ampicillin / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology*; D058491:Bacterial Load / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D006087:Graft vs Host Reaction / Q000187:drug effects / Q000276:immunology*; D007156:Immunologic Memory / Q000187:drug effects; D008088:Listeriosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000382:microbiology / Q000637:transplantation*; D013997:Time Factors
D000941:Antigens; D000667:Ampicillin; D010047:Ovalbumin
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