During acute graft versus host disease CD28 deletion in donor CD8+ , but not CD4+ , T cells maintain antileukemia responses in mice

Abstract

Donor lymphocyte infusions together with allogeneic hematopoietic stem cell transplantation are routinely used as second-line treatment for hematological malignancies. Mature T cells in the graft crucially mediate a graft versus leukemia (GvL) response, but also attack healthy tissues in the recipient leading to potentially life-threatening acute graft versus host disease. Using inducible CD28 knockout C57BL/6 mice as T-cell donors, we have now assessed whether CD28 costimulation of donor CD4⁺ and/ or CD8⁺ T cells is required for an efficient GvL effect after allogeneic T-cell transplantation into BALB/c recipients. Our results show that CD28 costimulation of donor CD8⁺ cytotoxic, but not CD4⁺ helper, T cells was dispensable for curing mice from the BCL-1 lymphoma. Therefore, donor lymphocyte infusion treated lymphoma-bearing BALB/c recipient mice showed enhanced long-term survival when receiving CD28-deficient as compared to wild-type donor CD8⁺ T cells together with wild-type conventional and regulatory CD4⁺ T cells. The same was observed when donor CD8⁺ and conventional and regulatory CD4⁺ T cells were CD28 deficient. Our data, thus, suggest that systemic CD28 blockade, for example, with the drug FR104 might also reduce acute graft versus host disease in patients after allogeneic hematopoietic stem cell transplantation, while maintaining the protective GvL response.

Keywords: Acute graft versus host disease; CD28 costimulation; CD4+ T cells; CD8+ T cells; Graft versus leukemia effect.