T-cell regenerative pathways after allogeneic HCT. Pretransplantation conditioning reduces the patient's existing naive (○) and memory (●) T cells. Post-HCT regeneration of peripheral T cells is accomplished by 2 mechanisms: (1) Cell numbers of residual host T cells and mature donor T cells transferred via a non-TCD stem cell allograft or via DLI expand initially in response to homeostatic signals or cognate antigen. Alloreactive donor T cells (which can mediate GVHD, graft-versus-leukemia, or both; dashed symbols) contribute also to the thymus-independent cell compartment. This T-cell pool is altered as a result of memory T-cell conversion, skewing of the TCR repertoire, and pool size contraction (broken lines indicate senescent T cells). (2) New naive T cells are generated from hematopoietic progenitors (yellow symbols) in a thymus-dependent regenerative mechanism. The stromal cells of the thymus (thymic medullary and cortical compartments are separated from each other by a dashed line) support the differentiation of descendants of thymic immigrants into mature T lymphocytes. Recent thymic emigrants (RTEs) expand in the periphery in response to homeostatic signals and after stimulation by their cognate antigen. Under physiologic conditions, the thymic export assures a constant and life-long supply with naive T cells harboring a diverse TCR repertoire. After allogeneic HCT, the thymus-dependent T-cell renewal is a slow process as it can take up to 12 to 24 months to be completed under favorable conditions. However, advanced age, conditioning, and GVHD impair thymus function and thus interfere with naive T-cell regeneration. The putative mechanisms are discussed in Figure 3.