The success of a hematopoietic stem cell transplantation (HSCT) partly relies on the beneficial graft-[1]versus-leukemia effect, mediated by alloreactive NK cells through their Killer-cell Immunoglobulin-like receptors (KIR). Conflicting results have been reported regarding the impact of the KIR immunogenetic system on HSCT outcomes with a scarcity of data interrogating the effect of KIR alleles. The first part of this thesis interrogates the predictive power of high-resolution KIR on to inform post transplant NK cell alloreactivity and analyze its impact on transplant outcomes. Donor KIR genes derived from a national cohort of 1247 donor/recipient pairs were determined at a high-resolution. Our study indicates that KIR high-resolution genotyping informs post-transplant outcomes mainly driven by KIR2DS4, KIR2DL2L3 and KIR3DL1 alleles.

Non-genetic factors have been shown as important inducers of immune system variations. However, the differential susceptibility and timing to immune modulation by non-genetic factors in reconstituting immune systems have not been fully understood yet. The second part of this thesis aims to dissect the temporal restoration of the NK cell and TCR repertoire post-[1]transplant and trace relations between immune state shifts and clinical events. Leveraging high-dimensional immunophenotyping and next-generation sequencing, we demonstrated that these repertoires establish at an early timepoint post-transplant and undergo coordinated inflationary changes upon CMV reactivation.