Pathways of T-cell regeneration in mice and humans: implications for bone marrow transplantation and immunotherapy

Much of our understanding of the immunobiology of bone marrow transplantation (BMT) has come from studies in young adult mice reconstituted with T-cell-depleted bone marrow after lethal irradiation. Recent evidence indicates, however, that the applicability of conclusions drawn from this model to human BMT may be limited. While mice retain essentially normal thymic function well past sexual maturity, humans show significant age-related declines in thymic function relatively early in life. Therefore, thymic-deficient mice may provide a more accurate model for study of the immunobiology of BMT. T-cell regeneration in thymic-deficient mice occurs primarily via antigen-driven expansion of mature peripheral T cells resulting in limited immune competence due to quantitative deficiencies in T-cell number and severe restriction in the diversity of the regenerated T-cell receptor (TCR) repertoire. Similarly, immune reconstitution in adult humans after BMT is marked by quantitative T-cell deficiencies, especially in the CD4+ subset, and loss of TCR diversity. Taken together, prevailing evidence suggests that thymic function is suboptimal in most BMT recipients, and that thymic-independent pathways of T-cell regeneration are generally limited in their ability to restore host immune competence. New strategies to enhance thymic function in man after BMT would hold great therapeutic potential.