The effects of age and GVHD on T-cell maturation and export. Age-related changes and GVHD affect T-cell development in prethymic, thymic, and post-thymic compartments. (A) Thymus function itself peaks in the first and second decades of life but then declines in the course of the involution process. During senescence, the sjTREC frequencies decline, whereas DβJβ species remain unchanged. The resultant decrease in the sj/β ratio (which falls below a value of 1:10) indicates lower TN proliferation, which hence explains the decline in RTE export in aged persons. (B) GVHD interference with intrathymic maturation is indicated by parallel decreases in DβJβTREC and sjTREC frequencies. The result is an unchanged sj/β ratio in peripheral blood T cells, which implies that thymopoiesis is affected either before TCRB chain rearrangement and TN proliferation and/or at a time subsequent to TCRAD rearrangement (eg, apoptosis of postrearrangement thymocytes). Acute GVHD therefore impairs thymic function independently from age. Both age-related thymus involution and GVHD are characterized by changes in the thymic stromal microenvironment. Lack of proper stromal function consequently leads to impairment of thymocyte development. In preclinical allogeneic HCT models, the demise of TECs (which may include the death of tolerance-inducing mTECs that express Aire) is linked to alloreactive donor T cells secreting intrathymically IFN-γ in response to activation by host TEC. Abbreviations and symbols are the same as in Figure 2. Broken lines indicate stromal cell death; and strikethrough arrows, deficient TEC function. BM indicates bone marrow.