HLA‐DR⁺ NK cells are mostly characterized by less mature phenotype and high functional activity

Abstract

NK cells change their phenotype and functional characteristics during activation. In this work, we searched for a relationship of HLA-DR expression with differentiation stages and functional activity of NK cells ex vivo and stimulated in vitro with IL-2 challenged with gene modified feeder K562 cells expressing membrane-bound IL-21 (K562-mbIL21). This stimulation technique has been described for NK cell expansion in clinical use. We have observed that HLA-DR expression in freshly isolated circulating NK cells was mostly associated with less differentiated CD56 CD57 cells, although in some individuals it could also be found in terminally differentiated CD57 cells. Ex vivo HLA-DR NK cells possessed better capacity to produce IFN-γ in response to cytokine stimulation compared to their HLA-DR counterparts. In vitro activation with IL-2 and K562-mbIL21 induces an increase in HLA-DR-positive NK cell proportion, again mostly among CD56 CD57 NK cells. This happened in particular due to appearance of HLA-DR expression de novo in HLA-DR-negative cells. Acquired in vitro HLA-DR expression was associated with NK cell proliferation activity, more intense cytokine-induced IFN-γ production, increased degranulation toward feeder cells, and higher expression of CD86 and NKG2D. Thus, stimulation with IL-2/K562-mbIL21 causes a significant phenotype and functional shift during NK cell activation and expansion.

Mass Cytometry Studies of Patients With Autoimmune Endocrine Diseases Reveal Distinct Disease-Specific Alterations in Immune Cell Subsets

“…This is an interesting finding, as it has been described that CD56 hi NK cells normally express HLA-DR to a higher degree than CD56 dim NK subsets (43,44). Intriguingly, it has been shown that CD56 dim HLA-DR + NK cells develop during pro-inflammatory conditions (45) and have better stimuli-induced secretion of IFN-γ than their HLA-DR − counterparts (44,45). Another function attributed to CD56 dim HLA-DR + NK cells is their capacity to induce differentiation of naïve CD4 + T cells into pre-central memory T cells (45).…”

“…An expansion of two CD56 dim NK subsets, expressing HLA-DR at a higher intensity than CD56 hi NK cells, was also detected in samples from patients with HT. This is an interesting finding, as it has been described that CD56 hi NK cells normally express HLA-DR to a higher degree than CD56 dim NK subsets (43,44). Intriguingly, it has been shown that CD56 dim HLA-DR + NK cells develop during pro-inflammatory conditions (45) and have better stimuli-induced secretion of IFN-γ than their HLA-DR − counterparts (44,45).…”

Age related defects in NK cell immunity revealed by deep immune profiling of pediatric cancer patients

“…Examining a broader range of NK phenotypic markers ( Figure 4A) confirmed these differences in maturity. Patients had a significantly higher proportion of NK cells bearing markers associated with NK immaturity (CD25, CD27, CD127 and HLA-DR) 34,35,36,37 and a significantly lower proportion of NK cells bearing markers associated with NK maturity (CD45RA and CD57) 38,39 . No difference was observed in the proportion of NK cells expressing the adhesion molecule CD11b 40 , the adhesion molecule and ectoenzyme CD38 41 nor CD161, expressed by a distinct subtype of pro-inflammatory NK cells 42 .…”

Regulation of NK-Cell Function by HLA Class II

“…NK cells have been shown to regulate immune cell responses of T cells (Waggoner et al, 2011;Cook et al, 2014;Crouse et al, 2015), antigen-presenting cells (Andrews et al, 2005;Moretta et al, 2005;Alter et al, 2010;Altfeld et al, 2011;Michel et al, 2012), and indirectly B cells (Rydyznski et al, 2015(Rydyznski et al, , 2018, all of which express HLA-II molecules. In addition, NK cells themselves are able to express HLA-II molecules (Sedlmayr et al, 1996;Erokhina et al, 2018;Costa-Garcia et al, 2019), implicating that a potential interaction between HLA-II and NK cell receptors can not only occur in trans but also in cis. The identification of HLA-II molecules as ligands for NK cell receptors now provides a possible molecular mechanism to investigate the immune cross-talk between NK cells and HLA-II-expressing immune cells, and the implications for immune responses against malignant cells and pathogens.…”