Partial break in tolerance of NKG2A−/LIR-1− single KIR+ NK cells early in the course of HLA-matched, KIR-mismatched hematopoietic cell transplantation

Abstract

Natural killer (NK) cell subpopulations from 8 HLA-matched but killer cell immunoglobulin-like receptor (KIR)/HLA-ligand-mismatched patient-donor pairs were analyzed in the course of allogeneic hematopoietic stem cell transplantation (HCT). The patients' post-transplantation NKG2A/LIR-1 NK cells, which expressed only inhibitory KIRs for which the patient had no HLA class I ligands, showed higher cytotoxic capacity than the NKG2A/LIR-1 NK cells lacking any inhibitory KIRs that remained tolerant throughout the course of HCT. The NKG2A NK cell subpopulations displayed the highest levels of cytotoxic activation, which appeared to be significantly enhanced in comparison with that in allogeneic graft's donors. LIR-1 NK cells were much more frequent after HCT than LIR-1 NK cells and LIR-1 expression on NKG2A or NKG2A NK cells was associated with significantly lower cytotoxic activities. Thus NKG2A/LIR-1 NK cells expressing only HLA-mismatched KIRs show a partial break in tolerance in the first year following HCT. The failure to exclude LIR-1 cells within the NKG2A NK cell subset in previous studies could explain the earlier conflicting results. Thus systemic immune activation in patients following HCT augments the GvL effect through both increasing overall NK cell activities and partially breaking tolerance of unlicensed NK cells.

Non‐KIR NK cell receptors: Role in transplantation of allogeneic haematopoietic stem cells

“…Moreover, an ILT2/ILT4 ligand, HLA‐G, was characterized by higher serum level after transplantation, as compared to the pre‐transplant period (Biedroń et al., 2015). ILT2 expression was also found to correlate with decreased significantly lower NK cell cytotoxicity, although ILT2‐negative NK cells were more frequent then ILT2‐positive cells after HSCT (Rathmann et al., 2017).…”

“…According to a recent study, NKp46 (together with NKG2D and CD226) may be crucial in cytotoxicity towards alloreactive T cells in aGvHD (Sheng et al, 2020). However, a study on 'unlicensed' (lacking inhibitory receptors) NK cells found that they exhibit an upregulation of the activating receptor NKp46, but not of NKG2D (Rathmann et al, 2017). This correlated with increased Epstein-Barr virus (EBV) viraemia (Yu et al, 2019).…”

LIR‐1 educates expanded human NK cells and defines a unique antitumor NK cell subset with potent antibody‐dependent cellular cytotoxicity

“…21 Among HLA class I, LIR-1 binds with the highest affinity to the non-classical molecule HLA-G, 22 whose role has mainly been highlighted in maternal-fetal tolerance. 23 The weak affinity for HLA class I and low responsiveness to missing-self by freshly isolated LIR-1 + NK cells 11,24 may explain why this receptor has not been broadly discussed with respect to NK cell targeting of tumor cells. Nonetheless, because it can signal via similar pathways such as NKG2A and inhibitory KIRs 25 and is expressed on 5-80% of NK cells, 26 LIR-1 remains of interest with respect to its potential role in NK cell education and immunotherapy of cancer.…”

In memoriam: Paul Fisch (1959–2018) our dear friend, pioneer of γδ T cell research, esteemed scientist, and dedicated clinician

“…This intriguing work was the beginning of several interesting discoveries in this area spanning over a decade, the most recent published in Blood in 2016 . Paul's additional non‐γδ T cell studies included thymoma‐associated immunodeficiencies and hematopoietic cell transplantations …”

“…18 Paul's additional non-cd T cell studies included thymoma-associated immunodeficiencies 19 and hematopoietic cell transplantations. 20 Paul was a quiet and humble person, with a demeanour that belied his vast intelligence. In his calm, friendly and reassuring way, he treated his conversation partners as equals, thereby instilling confidence in those who sought him out.…”