(A) Infusion of donor HSCs in patients with T and NK lymphocyte–negative and B lymphocyte–positive SCID leads to long-term thymopoiesis with a diverse T-lymphocyte receptor repertoire secondary to donor T-lymphocyte progenitor engraftment in the thymus. Donor HSCs do not engraft due to lack of space in the stem cell niche. (B) Donor HSCs infused into patients with T and B lymphocyte–negative and NK lymphocyte-positive SCID fail to engraft due to lack of space in the stem cell niche or in the thymus. Neither T nor B lymphopoiesis occurs, and patients are left with a nonrenewable limited T-lymphocyte repertoire and poor lymphoid immuno-reconstitution. (C) Fetal administration of anti-c-Kit receptor (ACK2) antibody to mice clears space within the HSC niche, facilitating engraftment of congenic donor HSCs in the neonatal period, permitting long-term immuno-reconstitution.