Relationship of NKG2C Copy Number with the Distribution of Distinct Cytomegalovirus-Induced Adaptive NK Cell Subsets

Abstract

CD94/NKG2C and lack of FcεRγ (FcRγ) expression are considered markers of the adaptive NK cell response to human CMV (HCMV) infection. Despite the fact that FcRγ− and NKG2Cbright NK cells share some phenotypic, epigenetic, and functional features, their relationship remains unclear. To address this issue, a systematic analysis of NKG2Cbright and FcRγ expression was carried out in NK cells from a cohort of healthy young adults (n = 81) considering NKG2C copy number, previously related to the magnitude of NKG2C+ NK cell expansion. NKG2Cbright and FcRγ− NK cells coincided in a subgroup of HCMV+ individuals, pointing to a common host–virus interaction pattern. Even though FcRγ loss was often confined to expanded NKG2Cbright NK cells, both markers appeared occasionally dissociated, consistent with the existence of distinct adaptive NK cell subsets. Remarkably, FcRγ loss was mostly accumulated within the NKG2Cbright subset in NKG2C+/+ subjects, whereas NKG2C−FcRγ− NK cell subpopulations were more frequently detected in NKG2C+/del donors and also in NKG2Cdel/del individuals, independently of activating killer Ig–like receptor expression. The distribution of other NK receptors (i.e., killer Ig–like receptor, LILRB1, or CD57) supported a sequential differentiation from NKG2CbrightFcRγ+ to NKG2CbrightFcRγ− NK cells. Noticeably, NKG2Cbright NK cells produced more TNF-α in response to Ab-dependent activation, regardless of their FcRγ levels. Moreover, the TNF-α response of NKG2C−FcRγ− subpopulations was lower than that of concurrent NKG2CbrightFcRγ− NK cells, further supporting that FcRγ levels and enhanced potential for cytokine production are uncoupled. Overall, our data extend the characterization of adaptive NK cell subsets that differentiate in response to HCMV, supporting a relationship between their distribution and NKG2C copy number.

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…HCMV‐adapted NK cells lacking NKG2C expression were also reported, most of them expressing activating KIRs 160, 161. Using a large NKG2C‐deficient cohort, it was recently demonstrated that adaptive NK cell responses could occur in the absence of both activating KIRs and NKG2C; however, these adaptive NK cells also largely display repertoire deviation toward self‐specific inhibitory KIR expression 162, 163. Also, self‐specific inhibitory KIR expression is not required for generating adaptive NK cells but is probably necessary for optimal functions.…”

Regulatory Functions of Natural Killer Cells in Multiple Sclerosis

“…Interestingly, infections not only activate NK cells but also shape NK cell functions (52–54). Thus, cytomegalovirus (CMV) induces expansion of NK cells that produce IL-10 in mice, to prevent excess of activation of CD8 T cells (55, 56).…”

The Memories of NK Cells: Innate-Adaptive Immune Intrinsic Crosstalk

“…Similarly to MCMV, human cytomegalovirus (HCMV) is able to induce the expansion of a NK subpopulation expressing the CD94/NKG2C activating receptor [57, 58]. The expansion of CD94/NKG2C + NK cells is believed to be linked to the recognition of a ligand on HCMV infected cells [59], but unlike in the mouse, this ligand has not been identified yet (Figure 3(a)). Surprisingly, this CD56 dim /CD16 bright /NKG2C + cell subset does not perform a specific cytotoxicity against fibroblasts infected with HCMV, as expected from memory cells.…”

“…Surprisingly, this CD56 dim /CD16 bright /NKG2C + cell subset does not perform a specific cytotoxicity against fibroblasts infected with HCMV, as expected from memory cells. Nevertheless, when stimulated by opsonized HCMV + target cells via CD16 receptor, CD56 dim /CD16 bright /NKG2C + cells display an enhanced ability to proliferate [60] and to secrete cytokines (in particular TNF-alpha) [59, 61]. Notably, humans lacking one KLRC2 allele that encodes NKG2C receptor had a compromised NK cell differentiation during HCMV infection, with altered adaptive response and high anti-HCMV IgG titers [62, 63].…”

“…Of note, CD56 dim /CD16 bright /NKG2C + NK cells develop a specific adaptive feature [59–61] characterized by an enhanced response via CD16 stimulation, which suggests an improved cooperation of memory-like NK cells with B cells. In line with this hypothesis, the T cell cytokine IL-21 has been described to induce both the development of CD56 dim /CD16 bright NK cells from CD34 + hematopoietic progenitors [12, 13, 93] and the switching of Ig produced by B cell to IgG1 and IgG3 isotypes [94], for which Fc γ RIIIA receptor (CD16 of NK cells) displays a higher affinity [95].…”