The Activating NKG2C Receptor Is Significantly Reduced in NK Cells after Allogeneic Stem Cell Transplantation in Patients with Severe Graft-versus-Host Disease

Abstract

Natural killer (NK) cells play a central role in the innate immune system. In allogeneic stem cell transplantation (alloSCT), alloreactive NK cells derived by the graft are discussed to mediate the elimination of leukemic cells and dendritic cells in the patient and thereby to reduce the risk for leukemic relapses and graft-versus-host reactions. The alloreactivity of NK cells is determined by various receptors including the activating CD94/NKG2C and the inhibitory CD94/NKG2A receptors, which both recognize the non-classical human leukocyte antigen E (HLA-E). Here we analyze the contribution of these receptors to NK cell alloreactivity in 26 patients over the course of the first year after alloSCT due to acute myeloid leukemia, myelodysplastic syndrome and T cell Non-Hodgkin-Lymphoma. Our results show that NK cells expressing the activating CD94/NKG2C receptor are significantly reduced in patients after alloSCT with severe acute and chronic graft-versus-host disease (GvHD). Moreover, the ratio of CD94/NKG2C to CD94/NKG2A was reduced in patients with severe acute and chronic GvHD after receiving an HLA-mismatched graft. Collectively, these results provide evidence for the first time that CD94/NKG2C is involved in GvHD prevention.

Quantity and Quality Reconstitution of NKG2A+ Natural Killer Cells Are Associated with Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation

“…As mentioned above, evidence for the recovery of NK cell receptor subsets after stem cell transplantation is scarce. In a prospective study Kordelas et al [19] monitored the frequencies of inhibitory receptor CD94/NKG2A expression in NK cells after the allo-HSCT course for 1 year and related the results to the occurrence of severe aGVHD or chronic GVHD in a cohort of 26 patients undergoing allo-HSCT. This study showed that the NKG2A receptor continuously decreased in the first year after allo-HSCT and that the NKG2A + subset was reduced in chronic GVHD patients.…”

“…Therefore, NKG2A + NK cells have been proposed to play a crucial role during the early stage of GVHD after transplantation. Previous studies have shown that the number of NKG2A + cells is decreased in patients with chronic GHVD after HSCT [19]. However, the relationship between NKG2A + NK cells and aGVHD has not been characterized.…”

Impact of MICA and NKG2D polymorphisms in HLA-fully matched related and unrelated hematopoietic stem cell transplantation

“…In contrast, these results were not found in patients with high-risk disease [14]. Moreover, expression of the activating NKG2C receptor (another member of the NKG2 family) is significantly lower in NK cells after HSCT in patients with severe GVHD [15]. We can therefore hypothesize that donor NK cells, with a low level of cytotoxic activity against host-type antigen-presenting cells, might promote GVHD via CD8+ cells [16].…”

Targeting NKG2A to elucidate natural killer cell ontogenesis and to develop novel immune-therapeutic strategies in cancer therapy

“…The disclosure of potential alloreactive uCD56 dim NK cells expanded early after allo‐ and haplo‐HSCT has arisen new important questions. Indeed, the constitutive expression of CD94/NKG2A on almost all NK cells early after HSCT represents a novel targetable immune‐checkpoint to boost NK cell alloreactivity early after transplant in order to prevent acute and chronic GvHD, the onset of opportunistic infection and to ensure an optimal engraftment …”