Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for a large number of malignant and nonmalignant (inherited) diseases of the hematopoietic system. Nevertheless, non-HLA identical transplantations are complicated by a severe T-cell immunodeficiency associated with a high rate of infection, relapse and graft-versus-host disease. Initial recovery of T-cell immunity following HSCT relies on peripheral expansion of memory T cells mostly driven by cytokines. The reconstitution of a diverse, self-tolerant, and naive T-cell repertoire, however, may take up to 2 years and crucially relies on the interaction of T-cell progenitors with the host thymic epithelium, which may be altered by GvHD, age or transplant-related toxicities. In this review, we summarize current concepts to stimulate reconstitution of a peripheral and polyclonal T-cell compartment following allogeneic transplantation such as graft manipulation (i.e., T-cell depletion), transfusion of ex vivo manipulated donor T cells or the exogenous administration of cytokines and growth factors to stimulate host-thymopoiesis with emphasis on approaches which have led to clinical trials. Particular attention will be given to the development of cellular therapies such as the ex vivo generation of T-cell precursors to fasten generation of a polyclonal and functional host-derived T-cell repertoire. Having been tested so far only in preclinical mouse models, clinical studies are now on the way to validate the efficacy of such T-cell progenitors in enhancing immune reconstitution following HSCT in various clinical settings. Stem Cells Translational Medicine  2019;00:1–8

Prolonged T-cell immunodeficiency following allogeneic transplantation is a major clinical problem leading to high rate of infectious complications and disease relapse. The present article discusses current strategies targeted to enhance immune reconstitution post-HSCT. In particular, this review emphasizes the importance of cellular therapies such as the injection of ex vivo generated T-cell progenitors to accelerate immune reconstitution following transplantation as this approach confers a polyclonal host repertoire without the risk of alloreactivity.