The CD94/NKG2A inhibitory receptor educates uterine NK cells to optimize pregnancy outcomes in humans and mice

Norman Shreeve,Delphine Depierreux,Delia Hawkes,James A Traherne,Ulla Sovio,Oisin Huhn,Jyothi Jayaraman,Amir Horowitz,Hormas Ghadially,John R.B Perry,Ashley Moffett,John G Sled,Andrew M Sharkey,Francesco Colucci

doi:10.1016/j.immuni.2021.03.021

Abstract

SummaryThe conserved CD94/NKG2A inhibitory receptor is expressed by nearly all human and ∼50% of mouse uterine natural killer (uNK) cells. Binding human HLA-E and mouse Qa-1, NKG2A drives NK cell education, a process of unknown physiological importance influenced by HLA-B alleles. Here, we show that NKG2A genetic ablation in dams mated with wild-type males caused suboptimal maternal vascular responses in pregnancy, accompanied by perturbed placental gene expression, reduced fetal weight, greater rates of smaller fetuses with asymmetric growth, and abnormal brain development. These are features of the human syndrome pre-eclampsia. In a genome-wide association study of 7,219 pre-eclampsia cases, we found a 7% greater relative risk associated with the maternal HLA-B allele that does not favor NKG2A education. These results show that the maternal HLA-B→HLA-E→NKG2A pathway contributes to healthy pregnancy and may have repercussions on offspring health, thus establishing the physiological relevance for NK cell education.Video

Highlights

Inhibitory receptors are vital checkpoints in the immune system
We show here that both splenic and uterine mouse natural killer (NK) cells expressed NKG2A but neither expressed NKG2C or NKG2E at embryonic day (E) 9.5, because cells from NKG2A-deficient Klrc1À/À mice on a C57BL/6 (B6) background did not stain with an antibody that reacts with NKG2A, NKG2C, and NKG2E (Figure S1A), consistent with published data (Rapaport et al, 2015)
We confirmed that all three subsets express NKG2A in early gestation, from $40% in cNK and tissue-resident uNK (trNK) to $60% in uterine ILC1 (uILC1) (Figure S1C)

Summary

Introduction

Inhibitory receptors are vital checkpoints in the immune system. In addition to suppressing activation, inhibitory natural killer (NK) cell receptors prime and calibrate NK cell function, a phenomenon known as NK cell education (Orr and Lanier, 2010) or licensing (Kim et al, 2005). There is a dimorphism at the À21 position of the leader sequence supplied by HLA-B (À21 HLA-B) encoding either threonine (T) or methionine (M) (Yunis et al, 2007; Vales-Gomez et al, 1999). This separates individuals into those who can provide functional peptides for high HLA-E expression and NKG2A ligation, which leads to education (MT or MM), and those who cannot (TT) and have low HLA-E expression (Horowitz et al, 2016). A role for this HLA-B dimorphism is emerging in HIV control, immunotherapy of patients with leukemia, and graft versus host disease (Ramsuran et al, 2018; Hallner et al, 2019; Petersdorf et al, 2020)

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