Natural killer (NK) cells have long been considered to be a homogenous population of innate lymphocytes with limited phenotypic and functional diversity. However, recent findings have revealed that ...these cells comprise a large number of distinct populations with diverse characteristics. Some of these characteristics may relate to their developmental origin, and others represent differences in differentiation that are influenced by factors such as tissue localization and imprints by viral infections. In this Review, we provide a comprehensive overview of the emerging knowledge about the development, differentiation and function of human NK cell populations, with a particular focus on NK cells in peripheral tissues.
Abstract
Background and Aims
Innate lymphoid cells ILC have been suggested to play a role in inflammatory bowel disease IBD. Here, we investigated the ILC compartment in intestinal biopsies and blood ...from distinct patient groups with Crohn’s disease CD and ulcerative colitis UC, either newly diagnosed or with disease established for at least 1 year. This approach allowed us to simultaneously investigate temporal, disease-specific, and tissue-specific changes in ILC composition in IBD.
Methods
ILC subset frequencies, phenotype, and transcription factor profile in blood and intestinal biopsies were investigated by multi-parameter flow cytometry analysis. Endoscopic disease severity was judged using the ulcerative colitis endoscopic index of severity and the simple endoscopic score for Crohn′s disease.
Results
The frequency of NKp44+ILC3 was decreased in inflamed tissue, both in patients with CD and those with UC, already at the time of diagnosis, and correlated with disease severity. Simultaneously, the frequency of ILC1 was increased in patients with CD, whereas the frequency of ILC2 was increased in patients with UC. However, in patients with established UC or CD, both ILC1 and ILC2 were increased. In contrast to the ILC composition in inflamed tissue, ILC in non-inflamed tissue or blood were unchanged compared with non-IBD controls. Finally, in patients undergoing treatment with an anti-α4β7 antibody the frequencies of ILC in peripheral blood remained unchanged.
Conclusions
We report both shared and distinct changes in ILC composition depending on diagnosis and disease duration. The alterations in ILC composition in IBD occur selectively at inflamed sites in the gut.
Expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self–major histocompatibility complex (MHC) class I molecules provides an educational signal that generates ...functional natural killer (NK) cells. However, the effects of activating KIRs specific for self-MHC class I on NK-cell education remain elusive. Here, we provide evidence that the activating receptor KIR2DS1 tunes down the responsiveness of freshly isolated human NK cells to target cell stimulation in donors homozygous for human leukocyte antigen (HLA)–C2, the ligand of KIR2DS1. The tuning was apparent in KIR2DS1+ NK cells lacking expression of inhibitory KIRs and CD94/NKG2A, as well as in KIR2DS1+ NK cells coexpressing the inhibitory MHC class I–specific receptors CD94/NKG2A and KIR2DL3, but not KIR2DL1. However, the tuning of responsiveness was restricted to target cell recognition because KIR2DS1+ NK cells responded well to stimulation with exogenous cytokines. Our results provide the first example of human NK-cell education by an activating KIR and suggest that the education of NK cells via activating KIRs is a mechanism to secure tolerance that complements education via inhibitory KIRs.
Although human T cells enter the peripheral lymphoid tissues early during fetal development, the adaptive immune system in the fetus has largely been regarded as functionally immature and ...unresponsive to stimulation. In this study, we show that depletion of fetal CD4+CD25(high) T regulatory (T(Reg)) cells, which are present at high frequency in fetal lymphoid tissues, results in vigorous T cell proliferation and cytokine production in vitro, even in the absence of exogenous stimulation. Analysis of CD4+ and CD8(+) T cell populations revealed a large subset of cells that expressed the early activation Ag, CD69. We show that this population represents a subset of highly reactive fetal T cells actively suppressed by fetal CD4+CD25(high) T(Reg) cells during development. These findings indicate that fetal T cells are, in the absence of CD4+CD25(high) T(Reg) cells, highly responsive to stimulation and provide evidence for an important role for CD4+CD25(high) T(Reg) cells in controlling T cell responses in utero.
Cellular heterogeneity can emerge from the expression of only one parental allele. However, it has remained controversial whether, or to what degree, random monoallelic expression of autosomal genes ...(aRME) is mitotically inherited (clonal) or stochastic (dynamic) in somatic cells, particularly in vivo. Here we used allele-sensitive single-cell RNA-seq on clonal primary mouse fibroblasts and freshly isolated human CD8
T cells to dissect clonal and dynamic monoallelic expression patterns. Dynamic aRME affected a considerable portion of the cells' transcriptomes, with levels dependent on the cells' transcriptional activity. Notably, clonal aRME was detected, but it was surprisingly scarce (<1% of genes) and mainly affected the most weakly expressed genes. Consequently, the overwhelming majority of aRME occurs transiently within individual cells, and patterns of aRME are thus primarily scattered throughout somatic cell populations rather than, as previously hypothesized, confined to patches of clonally related cells.
The live attenuated yellow fever virus (YFV) 17D vaccine provides a good model to study immune responses to an acute viral infection in humans. We studied the temporal dynamics, composition, and ...character of the primary human T cell response to YFV. The acute YFV-specific effector CD8 T cell response was broad and complex; it was composed of dominant responses that persisted into the memory population, as well as of transient subdominant responses that were not detected at the memory stage. Furthermore, HLA-A2- and HLA-B7-restricted YFV epitope-specific effector cells predominantly displayed a CD45RA(-)CCR7(-)PD-1(+)CD27(high) phenotype, which transitioned into a CD45RA(+)CCR7(-)PD-1(-)CD27(low) memory population phenotype. The functional profile of the YFV-specific CD8 T cell response changed in composition as it matured from an effector- to a memory-type response, and it tended to become less polyfunctional during the course of this transition. Interestingly, activation of CD4 T cells, as well as FOXP3(+) T regulatory cells, in response to YFV vaccination preceded the kinetics of the CD8 T cell response. The present results contribute to our understanding of how immunodominance patterns develop, as well as the phenotypic and functional characteristics of the primary human T cell response to a viral infection as it evolves and matures into memory.
Expression of non-rearranged HLA class I-binding receptors characterizes human and mouse NK cells. The postulation of the missing-self hypothesis some 30 years ago triggered the subsequent search and ...discovery of inhibitory MHC-receptors, both in humans and mice. These receptors have two functions: (i) to control the threshold for NK cell activation, a process termed "licensing" or "education," and (ii) to inhibit NK cell activation during interactions with healthy HLA class I-expressing cells. The discovery of activating forms of KIRs (aKIR) challenged the concept of NK cell tolerance in steady state, as well as during immune challenge: what is the biological role of the activating KIR, in particular when NK cells express aKIRs in the absence of inhibitory receptors? Recently it was shown that aKIRs also participate in the education of NK cells. However, instead of lowering the threshold of activation like iKIRs, the expression of aKIRs has the opposite effect, i.e., rendering NK cells hyporesponsive. These findings may have consequences during NK cell response to viral infection, in cancer development, and in the initial stages of pregnancy. Here we review the current knowledge of activating KIRs, including the biological concept of aKIR-dependent NK cell education, and their impact in health and disease.
ABSTRACT
CD8
+
T cells are believed to play an important role in the control of human immunodeficiency virus type 1 (HIV-1) infection. However, despite intensive efforts, it has not been possible to ...consistently link the overall magnitude of the CD8
+
T-cell response with control of HIV-1. Here, we have investigated the association of different CD8
+
memory T-cell subsets responding to HIV-1 in early infection with future control of HIV-1 viremia. Our results demonstrate that both a larger proportion and an absolute number of HIV-1-specific CD8
+
CCR7
−
CD45RA
+
effector memory T cells (T
EMRA
cells) were associated with a lower future viral load set point. In contrast, a larger absolute number of HIV-1-specific CD8
+
CCR7
−
CD45RA
−
effector memory T cells (T
EM
) was not related to the viral load set point. Overall, the findings suggest that CD8
+
T
EMRA
cells have superior antiviral activity and indicate that both qualitative and quantitative aspects of the CD8
+
T-cell response need to be considered when defining the characteristics of protective immunity to HIV-1.
Natural killer (NK) cells are cytotoxic lymphocytes and play a vital role in controlling viral infections and cancer. In contrast to B and T lymphopoiesis where cellular and regulatory pathways have ...been extensively characterized, the cellular stages of early human NK cell commitment remain poorly understood. Here we demonstrate that a Lin−CD34+CD38+CD123−CD45RA+CD7+CD10+CD127− population represents a NK lineage-restricted progenitor (NKP) in fetal development, umbilical cord blood, and adult tissues. The newly identified NKP has robust NK cell potential both in vitro and in vivo, generates functionally cytotoxic NK cells, and lacks the ability to produce T cells, B cells, myeloid cells, and innate lymphoid-like cells (ILCs). Our findings identify an early step to human NK cell commitment and provide new insights into the human hematopoietic hierarchy.
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•CD34+CD38+CD123−CD45RA+CD7+CD10+CD127− cells represent NK lineage progenitor (NKP)•NKP is located downstream of LMPP and CLP within the human hematopoietic hierarchy•NKP generates mature functional NK cells in vitro and in vivo but no other lineages•NKP is conserved throughout ontogeny and is found in human adult and fetal tissues
Natural killer (NK) cells are innate lymphocytes specialized in cytotoxicity against tumor and virus-infected cells and cytokine production, but their development in humans is not well understood. Sitnicka and colleagues identify a novel hematopoietic progenitor conserved throughout ontogeny that has robust NK cell potential, restricted to NK lineage.
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