Limiting the Amount and Duration of Antigen Exposure during Priming Increases Memory T Cell Requirement for Costimulation during Recall

Abstract

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.

Candida-Elicited Murine Th17 Cells Express High CTLA-4 Compared with Th1 Cells and Are Resistant to Costimulation Blockade

“…We chose to use CTLA-4 Ig in the presence of anti-CD154 Ab because in this antigen-specific model of graft rejection CTLA-4 Ig is ineffective at providing long-term graft survival (32). In the presence of costimulation blockade, M.Tb OVA immunized mice were protected from graft rejection for > 60 days post transplantation (Figure 1D).…”

Transplantation Tolerance: Memories That Haunt Us

“…Although immunologically naïve recipients can be rendered permanently tolerant of their allogra s a er a regimen that involves pretransplant conditioning of the recipient with irradiation or chemotherapeutic agents, intravenous infusion of a donor-derived cell source, and simultaneous blockade of T cell costimulatory pathways, mice containing donor-reactive memory T cells are resistant to tolerance induction. However, the degree and duration of antigen exposure, context of antigen presentation, and type of pathogen infection can all in uence the ability of donor-reactive memory T cells to precipitate rejection (18,19). Another parameter that potentially inuences donor-reactive memory T cell quality is the a nity of the cross-reactive population for the allo-peptide MHC complex: It is possible that low-a nity donor-reactive memory T cells may be easier to tolerize than high-a nity clones.…”

The Microbiome, Systemic Immune Function, and Allotransplantation

“…Allograft vasculopathy in murine cardiac transplant models (parental to F 1 ) infected with lymphocytic choriomeningitis virus (LCMV) in the complete absence of T and B lymphocytes (RAG Ϫ/Ϫ ) was found to be mediated by NK cells; depletion of NK cells abrogated vasculopathy (56). Thus, pathogen-specific effects on allograft survival relate to the timing, duration, and intensity of innate and adaptive responses (57).…”