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.

Selective CD28 blockade attenuates CTLA-4–dependent CD8+ memory T cell effector function and prolongs graft survival

“…First, these data demonstrate differences in the quantity and quality of donor-reactive memory CD8 + T cells elicited via distinct types of exposure and highlight the fact, as we previously reported (31), that the heterogeneity of alloreactive CD8 + T cell memory might necessitate tailored therapeutic targeting for optimal control. We previously showed that antagonism of either LFA-1 or VLA-4 synergized with a regimen consisting of CTLA-4 Ig and anti-CD154 to prolong survival in animals possessing donor-specific CD8 + memory T cells elicited via the Listeria-OVA system used here (54).…”

“…As we have previously published, antigen-specific T cell responses peaked at day 10 and formed a detectable population of memory CD8 + T cells by day 30 (ref. 31 and data not shown). Skin graft rejection in this model is dependent on donor-reactive Thy1.1 + memory CD8 + T cells because administration of an anti-Thy1.1-depleting antibody eliminated the rejection response (31).…”

“…31 and data not shown). Skin graft rejection in this model is dependent on donor-reactive Thy1.1 + memory CD8 + T cells because administration of an anti-Thy1.1-depleting antibody eliminated the rejection response (31). On day 30 after infection, animals were challenged with an OVA-expressing skin graft and treated with immunosuppressive regimens consisting of an integrin blocker (anti-VLA-4) combined with either CTLA-4 Ig or anti-CD28 dAb ( Figure 1C).…”

“…In light of these possibilities, we sought to determine the effect of a selective CD28 blocker in an experimental model of transplantation in which rejection is mediated by donor-reactive memory CD8 + T cells (31). Previous studies have examined the impact of selective CD28 blockers in both mouse and NHP models of transplantation and autoimmunity (32)(33)(34)(35)(36)(37).…”

CTLA4-Ig in combination with FTY720 promotes allograft survival in sensitized recipients

“…While some studies suggest that memory T cells do not require costimulation for reactivation, others have reported that costimulation remains necessary for their recall activation and expansion in vivo (40)(41)(42)(43)(44)(45). By carefully tracking endogenous donor-specific T cells using the IFN-γ ELISPOT assay as well as with fluorescently labeled 2W:I-A b and OVA:K b multimers, we observed that CTLA4-Ig was able to prevent the expansion of donor-specific T cells in sensitized mice.…”