Abstract
Human lymphoid tissues harbor, in addition to CD56bright and CD56dim natural killer (NK) cells, a third NK cell population: CD69+CXCR6+ lymphoid tissue (lt)NK cells. The function and development of ltNK cells remain poorly understood. In this study, we performed RNA sequencing on the three NK cell populations derived from bone marrow (BM) and blood. In ltNK cells, 1,353 genes were differentially expressed compared to circulating NK cells. Several molecules involved in migration were downregulated in ltNK cells: S1PR1, SELPLG and CD62L. By flow cytometry we confirmed that the expression profile of adhesion molecules (CD49e−, CD29low, CD81high, CD62L−, CD11c−) and transcription factors (Eomeshigh, Tbetlow) of ltNK cells differed from their circulating counterparts. LtNK cells were characterized by enhanced expression of inhibitory receptors TIGIT and CD96 and low expression of DNAM1 and cytolytic molecules (GZMB, GZMH, GNLY). Their proliferative capacity was reduced compared to the circulating NK cells. By performing gene set enrichment analysis, we identified DUSP6 and EGR2 as potential regulators of the ltNK cell transcriptome. Remarkably, comparison of the ltNK cell transcriptome to the published human spleen-resident memory CD8+ T (Trm) cell transcriptome revealed an overlapping gene signature. Moreover, the phenotypic profile of ltNK cells resembled that of CD8+ Trm cells in BM. Together, we provide transcriptional and phenotypic data that clearly distinguish ltNK cells from both the CD56bright and CD56dim NK cells and substantiate the view that ltNK cells are tissue-resident cells, which are functionally restrained in killing and have low proliferative activity.
Highlights
The recent identification of tissue-resident lymphocytes in both human and mice contributes to our extending knowledge on the heterogeneity of innate and adaptive lymphocyte populations
The majority of natural killer (NK) cell studies focused on circulating NK cells, which resulted in the classical subdivision of NK cells in the CD56bright and CD56dim NK cell subsets
We recently defined a non-circulating NK cell population, based on the combined expression of CD69 and CXCR6, which resides in lymphoid tissues
Summary
The recent identification of tissue-resident lymphocytes in both human and mice contributes to our extending knowledge on the heterogeneity of innate and adaptive lymphocyte populations. Subsets of the human innate natural killer (NK) cells exhibit a tissue-resident phenotype as demonstrated in various organs, including the uterus, liver, tonsils, bone marrow (BM), spleen, and lymph nodes [6,7,8,9,10,11,12]. The remaining non-resident (circulating) NK cells are subdivided into two populations based on CD56 and CD16 expression: CD56brightCD16−/+ and CD56dimCD16+ [15]. The function of tissue-resident NK cells is still unknown, since they are neither good producers of IFN-γ nor potent killers [7, 12]
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