Deciphering the biology of KIR2DL3+ T lymphocytes that are associated to relapse in haploidentical HSCT

Gaëlle David,Alexandre Walencik,Thierry Guillaume,Patrice Chevallier,Christelle Retière,Pierre Mérieau,Nolwenn Legrand,Zakia Djaoud,Catherine Willem,Katia Gagne

doi:10.1038/s41598-021-95245-7

Abstract

KIR are mainly expressed on NK cells and to a lesser extent on T lymphocytes. Although the KIR NK cell repertoire was well explored in haploidentical Hematopoietic Stem Cell Transplantation (HSCT), KIR T cell compartment remains to be investigated in this context. In this study, the investigation of NK receptors on T lymphocytes during immune reconstitution after T-cell-replete haploidentical HSCT with Post-Transplant Cyclophosphamide (PTCy) has shown a significant increase of KIR2DL2/3+ T cell frequency at day 25. This was especially observed at day 30 in recipients who relapsed. IL-15 but not IL-12 increased in vitro KIR+ T cell expansion suggesting that the raised IL-15 serum concentration observed after PTCy in haploidentical HSCT might increase KIR+ T cell frequency. Moreover, investigations from healthy blood donors showed a higher inhibiting effect of KIR2DL3 on CMV specific T cell response against allogeneic than autologous C1+ target cells. The association of KIR+ T cell subset with relapse may suggest that inhibitory KIR2DL2/3 limit anti-leukemic effect of specific T lymphocytes at this early step of immune reconstitution. Further phenotypic and mechanistic investigations on this cell subset from a broader cohort of HSCT recipients should clarify its potential implication in relapse occurrence. Our results demonstrate that KIR-HLA interactions known to modulate NK cell functions also modulate T cell immune responses in the context of allogeneic HSCT.

Highlights

KIR are mainly expressed on Natural Killer (NK) cells and to a lesser extent on T lymphocytes
We observed an increased frequency of KIR2DL2/3/S2+ T cells during immune reconstitution after Hematopoietic Stem Cell Transplantation (HSCT), at day 25 compared to graft (0.007) and day 5 (0.001) and at day 30 compared to day 5 (0.02) (Fig. 1A)
We reported an increased frequency of KIR2DL2/3+ T lymphocytes in the predominant C D56− cell compartment during immune reconstitution after T-replete haploidentical HSCT with Post-Transplant Cyclophosphamide (PTCy) with a significant increase around day 25

Summary

Introduction

KIR are mainly expressed on NK cells and to a lesser extent on T lymphocytes. the KIR NK cell repertoire was well explored in haploidentical Hematopoietic Stem Cell Transplantation (HSCT), KIR T cell compartment remains to be investigated in this context. The investigation of NK receptors on T lymphocytes during immune reconstitution after T-cell-replete haploidentical HSCT with Post-Transplant Cyclophosphamide (PTCy) has shown a significant increase of KIR2DL2/3+ T cell frequency at day 25. This was especially observed at day 30 in recipients who relapsed. The Immunoglobulin superfamily clusters numerous major molecules implicated in T and NK cellular immunity as CD3, CD4, CD8, HLA class I, HLA class II molecules and KIR (Killer cell Immunoglobulin like Receptors) These latter are mainly expressed on Natural Killer (NK) cells and constitute key receptors engaged with HLA class I molecules to modulate NK cell responses. The minor CD56+ T lymphocyte subset that share common phenotypic markers with NK cells, express KIR and K IR+ CD56+ T cell frequency can drastically increase with CMV infection[22]

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Results

Conclusion