Figure 1. Schematic iNKT cell reconstitution dynamics and correlation with disease control following hHSCT in pediatric leukemia patients. A longitudinal analysis of iNKT cell reconstitution in relation to disease remission was performed monthly for 18 mo post-hHSCT in 22 children affected by leukemia and myelodisplasia. This data were integrated by a cross-sectional analysis of iNKT cell frequency and maturation in a second cohort of 11 leukemia patients that were in stable remission from 1 to 8 y after transplantation. (A) Schematic illustration of the transplantation physiology in case of HLA-haploidentical conditions. Donor CD34⁺ HSC are T cell depleted to reduce the risk of GVHD due to donor/recipient HLA barrier. Patients are myeloablated to eradicate malignant cells and eliminate the endogenous immune system and then infused with purified CD34⁺ HSC. Pro-thymocytes, originated from transplanted HSC that have reached the bone marrow, colonize the thymus and generate T and iNKT cells that are exported in the periphery. iNKT cells are detectable in periphery of patients maintaining remission as early as 3 mo post-hHSCT and reach an average of > 10 iNKT/10⁶ T cells in the 18 mo observation time, whereas iNKT cells fail to reconstitute in relapsing patients, remaining on average < 20 iNKT/10⁶ T cells. (B) Immunoreconstitution dynamics of human iNKT cell following hHSCT. The left panel depicts the different dynamics followed by the CD4⁺ and CD4^- iNKT cell subsets. The CD4⁺ emerge before the CD4^- ones in the periphery and remain the dominant subset up to 4–5 y post-transplant. The CD4^- cells undergo a massive expansion around 7 y post-hHSCT, resulting in the CD4^- > CD4⁺ iNKT cell ratio typical of adult healthy individuals. The right panel shows the dynamics of the terminal NK-maturation of the two iNKT cells subsets, as defined by the acquisition of CD161 (NKPR1a-c). Both CD4⁺ and CD4^- subsets emerge in the periphery with an immature CD161^- phenotype. The CD4^- subset matures markedly more rapidly than the CD4⁺ cells and reaches adult CD161-expression levels already by 2 y post-hHSCT, whereas the CD4⁺ iNKT cells have not yet completed their NK-maturation after 7 y post-transplantation.