Extrathymic T cell development and donor hematopoietic reconstitution after bone marrow transplantation with adoptive T cell precursor therapy

Successful bone marrow transplantation (BMT) requires cytoreductive conditioning to reduce malignant burden and facilitate donor hematopoietic cell engraftment. Consequently, healthy recipient immune cells are eliminated, reducing immune incompetence after BMT. Moreover, older patients suffer prolonged T cell deficiency due to the combination of age-related thymic involution and damage caused by cytoreductive conditioning. Efforts to minimize conditioning in order to limit toxicity are associated with increased graft failure. Strategies to enhance immune reconstitution after transplantation, including adoptive T cell precursor (preT) therapy, are making their way to the clinic after successful preclinical investigation. However, the sources of immune regeneration after transplantation into recipients without thymic function, such as elderly patients, are incompletely understood. We use murine models to study the mechanism of thymus-independent T cell development after transplantation, and the effects of adoptive preT therapy on extrathymic T cell development and donor immune reconstitution.;We demonstrate that mesenteric lymph nodes support extrathymic development of CD4+CD8+ (double positive, DP) T cell progenitors in euthymic and athymic BMT recipients. Extrathymic T cell development contributes an increased proportion of DP cells in aging mice, as thymopoiesis was more dramatically reduced than extrathymic development. In athymic BMT recipients, CD8+ T cells have a broad Vbeta repertoire and naive CD62L+CD44- phenotype. CD4+ T cells have a restricted repertoire with an atypical CD62L-CD44 - phenotype. Extrathymic-derived T cells mount functional proliferative and cytokine responses in vitro. Moreover, virus-specific extrathymic-derived T cells provide protection against lymphocytic choriomeningitis virus in vivo.;PreT enhance donor-derived immune reconstitution in the bone marrow niche, thymus, and spleen. Despite their T cell commitment, preT enhance recovery of BM-derived B cells, NK cells, dendritic cells, and myeloid cells, in addition to T cells. Adoptive preT therapy rescues recipients of exceedingly low doses of lineage-c-kit+Sca-1+ cells from mortality. PreT express Cxcl12, which may contribute to their beneficial influence on BM-derived cells. Finally, in a model of reduced radiation intensity, preT enable greater engraftment of donor BM cells.;These data indicate that adoptive preT therapy undergo extrathymic T cell development, an important mechanism of T cell regeneration after BMT, and aid BM-derived reconstitution in clinically relevant models.