Open Access, Peer-reviewed
pISSN 1598-2629 eISSN 2092-6685
Indexed in PubMed, Scopus and SCIE
    Immune Netw. 2023 Feb;23(1):e8. English.
    Published online Feb 20, 2023.
    https://doi.org/10.4110/in.2023.23.e8
    Copyright © 2023. The Korean Association of Immunologists
    Review

    Human CD8+ T-Cell Populations That Express Natural Killer Receptors

    June-Young Koh,1,2,† Dong-Uk Kim,1,† Bae-Hyeon Moon,1,† and Eui-Cheol Shin1,3
      • 1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
      • 2Genome Insight, Inc., Daejeon 34051, Korea.
      • 3The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Korea.
    • Correspondence to Eui-Cheol Shin. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), 245 Daehak-ro, Yuseong-gu, Daejeon 34141, Korea. Email: ecshin@kaist.ac.kr

      †These authors contributed equally.
    Received December 28, 2022; Revised February 07, 2023; Accepted February 07, 2023.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    CD8+ T cells are activated by TCRs that recognize specific cognate Ags, while NK-cell activation is regulated by a balance between signals from germline-encoded activating and inhibitory NK receptors. Through these different processes of Ag recognition, CD8+ T cells and NK cells play distinct roles as adaptive and innate immune cells, respectively. However, some human CD8+ T cells have been found to express activating or inhibitory NK receptors. CD8+ T-cell populations expressing NK receptors straddle the innate-adaptive boundary with their innate-like features. Recent breakthrough technical advances in multi-omics analysis have enabled elucidation of the unique immunologic characteristics of these populations. However, studies have not yet fully clarified the heterogeneity and immunological characteristics of each CD8+ T-cell population expressing NK receptors. Here we aimed to review the current knowledge of various CD8+ T-cell populations expressing NK receptors, and to pave the way for delineating the landscape and identifying the various roles of these T-cell populations.

    Keywords
    CD8-Positive T-Lymphocytes; Natural Killer Cell Receptors; CD56 Antigen; Receptors, KIR; NKG2A Receptor; NKG2C Receptor

    INTRODUCTION

    Although both human NK and CD8+ T cells are representative cytotoxic lymphocytes, they have distinct characteristics as innate and adaptive immune cells, respectively. NK-cell activation is regulated by a balance between signals from germline-encoded activating and inhibitory NK receptors. Activating NK receptors—such as NKG2D, NKp44, NKp30, and NKG2C—recognize ligands that are mainly expressed on aberrant cells, e.g., virus-infected, transformed, or stressed cells. On the other hand, inhibitory NK receptors—such as killer cell immunoglobulin-like receptors (KIRs) and NKG2A—recognize MHC ligands that are expressed on normal healthy cells (1, 2). As adaptive immune cells, CD8+ T cells are activated by TCRs that recognizes specific epitopes presented by MHC class I (MHC-I) molecules and exert effector functions (3). The CD8+ T-cell population exhibits a highly diverse TCR repertoire, enabling CD8+ T cells to respond against many different Ags.

    Some subsets of T cells such as mucosal-associated invariant T cells, invariant natural killer T cells and γδ T cells express TCRs with limited diversity and exert innate-like functions. Apart from those subsets, CD8+ T cells can express activating or inhibitory NK receptors, including KIRs, NKG2A, and NKG2C. However, studies have not yet comprehensively elucidated the immunological characteristics of CD8+ T-cell subpopulations expressing each NK receptor.

    In this review, we provide an overview of CD8+ T-cell subpopulations expressing NK receptors. First, we describe CD8+ T cells expressing CD56, with regard to their innateness and NK receptor expression. Next, we provide a structured review of CD8+ T-cell subpopulations expressing KIR, NKG2A, or NKG2C. Finally, we discuss the physiological and pathological roles of CD8+ T-cell subpopulations expressing NK receptors. We do not describe NKG2D because NKG2D is expressed by all types of human CD8+ T cells, not by a CD8+ T-cell subpopulation.

    CD8+ T CELLS EXPRESSING CD56

    CD56—also known as neural cell adhesion molecule (NCAM)—is the first characterized immunoglobulin superfamily member engaged in cell adhesion (4). CD56 serves as a classical lineage marker for human NK cells, which are defined as CD3−CD56+ lymphocytes (5). Additionally, the CD56 expression level is used to define functionally distinct subsets of NK cells—with a CD56bright NK-cell subset showing elevated cytokine production (6, 7), and a CD56dim NK-cell subset exhibiting enhanced cytotoxicity and a mature differentiation status (8).

    In this background, early investigators used the term “natural T cells” to describe CD56-expressing T cells (9, 10, 11). This CD56+ natural T-cell population comprises heterogeneous T-cell subsets, including γδ T cells and CD4+ T cells, but mainly CD8+ T cells with conventional TCRs (11, 12). CD56+ T cells are distinguished from CD56− T cells and invariant T cells, in terms of TCR clonality, surface protein phenotypes, and genome-wide transcriptional patterns. Compared with CD56− T cells, CD56+ T cells exhibit higher expressions of NK-cell-related molecules (e.g., CD16, CD94/NKG2, NKG2D, CD122, and DNAM-1) and granzyme B (12). With regards to TCR diversity, CD56+ T cells exhibit a considerably restricted TCRVβ spectrum compared to CD56− T cells, but a more diverse spectrum than invariant T cells. CD56+ T cells expand in response to IL-2 synergized with IL-12 (13). They also exhibit a potent capacity for T helper 1 cytokine production, and exert TCR-independent cytotoxicity following stimulation with mitogen and IL-2 (10). Based on these innate-like features, it has been suggested that CD56+ T cells may contribute to rapid immune responses against viruses, like innate immune cells. CD56+ T cells have been reported to inhibit hepatitis C virus replication in hepatocytes (14). The frequency of CD56+ T cells in peripheral blood is higher among patients with cytomegalovirus (CMV) infection compared to healthy donors (15).

    Our research group recently identified a distinct CD8+ T-cell subpopulation showing high CD56 expression without CD161 expression (CD56hiCD161−CD8+ T cells), which is characterized by high expression of NK-related molecules and a uniquely restricted TCR repertoire (Fig. 1). The frequency of these cells within the liver sinusoidal CD8+ T-cell population is significantly increased among patients with hepatitis B virus (HBV)-related chronic liver disease (16). CD56hiCD161−CD8+ T cells mainly exhibit a CCR7−CD45RA− effector memory phenotype, and include a higher frequency of CD69+ cells, which are tissue resident memory T (TRM) or TRM-like cells, compared to other effector memory CD8+ T cells. CD56hiCD161−CD8+ T cells exhibit weak responsiveness to TCR stimulation, but they show high expression of various NK receptors (e.g., CD94, KIRs, and NKG2C) and exert NKG2C- or NKG2D-mediated effector functions even in the absence of TCR stimulation. Additionally, CD56hiCD161−CD8+ T cells are highly responsive to innate cytokines (e.g., IL-12/18 and IL-15) in the absence of TCR stimulation. The CD56hiCD161−CD8+ T-cell population resembles previously described CD161−CD56+ regulatory CD8+ T cells (17). Further studies are needed to elucidate the roles of CD56hiCD161−CD8+ T cells in immune responses to microbial pathogens or immunopathology.

    Figure 1
    Innate-like features of the CD56hiCD161−CD8+ T-cell population. Our group recently reported a CD8+ T-cell population marked with high CD56 expression without CD161 expression (CD56hiCD161−CD8+ T cells). These CD56hiCD161−CD8+ T cells are distinguished from other CD8+ T cells in terms of their innate-like features. This CD8+ subpopulation exhibits high expressions of various NK receptors, and exerts NK-receptor mediated effector functions in a TCR-independent manner. Additionally, these CD56hiCD161−CD8+ T cells show increased responsiveness to stimulation with innate cytokines, including IL-12/18 and IL-15.

    CD8+ T CELLS EXPRESSING KIRs

    Virus-infected or transformed host cells tend to lose their MHC-I expression (termed “missing-self”). These aberrant cells with MHC-I downregulation are targeted by NK cells. When target cells express sufficient levels of MHC-I, inhibitory KIRs (receptors for MHC-I) deliver inhibitory signals to NK cells, which does not occur when target cells lose MHC-I expression (18). KIRs are polygenic and polymorphic Ig superfamily receptors, which can recognize distinct MHC-I molecules that are also polygenic and polymorphic. Inhibitory KIRs contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic domains, which suppress signaling delivered by activating receptors (19, 20).

    KIRs can be expressed on TCRαβ+CD8+ T cells as well as NK cells (21), and can exert a suppressive function in both cell types. Engagement of KIRs with MHC-I ligands reduces the TCR-mediated phosphorylation of ZAP-70 and LAT and downstream signaling pathways (22). This decreases the TCR-triggered effector functions of CD8+ T cells, in terms of cytokine secretion (23, 24) and cytotoxicity (24, 25, 26). On the other hand, KIRs might contribute to CD8+ T-cell survival by suppressing activation-induced cell death (27, 28). Furthermore, several studies suggest that KIR+CD8+ T cells show intrinsic functional impairment, at least against TCR stimulation. Impairment of proliferation and cytokine secretion have been reported even in the absence of KIR engagement (29, 30, 31).

    KIR+CD8+ T cells exhibit the surface phenotypes of CCR7−CD45RA+ effector memory T (TEMRA) cells, known as terminally differentiated T cells (32, 33), and CD28−CD57+ replicative-senescent T cells (30, 34). They also express high levels of cytotoxic molecules, such as perforin (29) and granzyme B (35). KIR+CD8+ T cells exhibit an increasing frequency with age (31, 36) and have a restricted TCR repertoire (26, 30, 37).

    Infection with CMV, one of the most prevalent latent viruses in human beings, is associated with expansion of the KIR+CD8+ T-cell population. Chan et al. (12) demonstrated that CMV-seropositive individuals have higher frequencies of KIR+CD56+ T cells compared to CMV-seronegative individuals. Moreover, CMV reactivation is associated with expansion of the KIR+CD56+ T-cell population in bone marrow transplant recipients. It was hypothesized that the KIR+ T cells in CMV-seropositive individuals are specific to CMV Ags. However, Björkström et al. (30) demonstrated that KIR expression is much lower (or virtually absent) on CMV pp65-specific CD45RA+CD57+CD8+ T cells compared to on the non-specific population. On the other hand, a recent report described KIR expression on the vast majority of HLA-E-restricted CMV UL40-specific CD8+ T cells (38).

    Besides in CMV infection, the KIR+CD8+ T-cell population expands in patients with HIV infection (39) and psoriasis (40). Additionally, the MHC allele-dependent expansion of KIR+CD8+ T-cell populations has been reported in cancer patients (41, 42). It remains unknown whether Ag recognition by TCR is required for expansion of the KIR+CD8+ T-cell population in patients with inflammation or infection.

    Recent studies have reported that KIR+CD8+ T cells function in regulating immune responses (Fig. 2). In 2021, Pieren et al. (31) reported that KIR+CD45RA+CD8+ T cells are regulatory CD8+ T cells, as was previously described in mice (43). Similar to CD4+ Tregs, KIR+CD45RA+CD8+ T cells exhibit high expressions of Helios and TIGIT. These cells also show upregulation of CD122, which is associated with CD8+ Tregs in mice. Pieren et al. (31) also demonstrated that KIR+CD45RA+CD8+ T cells can dose-dependently regulate the proliferation of KIR−NKG2A− conventional CD8+ T cells. More recently, Li et al. (37) also reported that KIR+CD8+ cells act as CD8+ Tregs. They found increased frequencies of KIR+CD8+ T cells in patients with autoimmune diseases and infections, such as celiac disease and coronavirus disease 2019 (COVID-19). When gliadin-specific CD4+ T cells from patients with celiac disease were stimulated with Ag, KIR+CD8+ T cells suppressed pathogenic CD4+ T-cell responses by killing pathogenic cells, without harming non-pathogenic CD4+ T cells. RNA sequencing of KIR+CD8+ T cells further revealed that human KIR+CD8+ T cells are the analogous population of mouse Ly49+CD8+ T cells (CD8+ Tregs). Further studies are required to elucidate how the KIR+CD8+ T-cell population size is regulated, and how these cells recognize pathogenic T cells.

    Figure 2
    KIR+CD8+ T cells as a regulator of immune responses. KIR+CD8+ T cells have been reported to be human CD8+ TREG cells, which can regulate or kill pathogenic T cells. Similar to CD8+ TREG cells of mice, human KIR+CD8+ T cells exhibit high expressions of the transcription factor Helios and IL-15 receptor β chain (CD122). They contain high amounts of cytotoxic molecules (perforin and granzyme B), and show restricted TCR usage. The mechanisms of how KIR+CD8+ T cells originate, and how they recognize pathogenic T cells, remain unknown.

    CD8+ T CELLS EXPRESSING NKG2A

    A member of the lectin family, NKG2A is an ITIM-bearing inhibitory receptor (44). NKG2A forms a heterodimer with CD94, and binds to HLA-E, which is expressed on most human tissues and complexed with peptides derived from the leader sequence of classical MHC-I (45, 46, 47). NKG2A is typically expressed on NK cells, but can also be expressed on CD8+ T cells (48, 49, 50). TCR stimulation induces NKG2A expression on CD8+ T cells in a manner synergized with cytokines, such as IL-12, IL-15, and TGF (51, 52, 53, 54, 55). NKG2A engagement suppresses effector functions of CD8+ T cells (49), as also observed in NK cells, and blockade of NKG2A or CD94 increases the cytotoxic activity of NKG2A-expressing CD8+ T cells (53).

    NKG2A has recently attracted attention as an immune checkpoint, similar to the well-known checkpoint receptors PD-1, TIGIT, and TIM-3 (56, 57). An anti-NKG2A monoclonal Ab, called monalizumab, has been developed (58, 59). Clinical trials investigating concomitant use of anti-PD-1/PD-L1 treatment and monalizumab have shown better clinical results in diverse cancers, including bladder cancer, non-small-cell lung cancer, and colorectal cancer (56, 60, 61). Chronic antigenic stimulation and persistent exposure to various cytokines in the tumor microenvironment reportedly induce NKG2A expression on tumor-infiltrating CD8+ T cells (51). Monalizumab reinvigorates the cytotoxic function of NKG2A+CD8+ T cells by blocking the interaction of NKG2A with HLA-E expressed on cancer cells. It has also been found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific CD8+ T cells from patients with severe COVID-19 express high NKG2A levels, and exert reduced effector functions (62).

    NKG2A and/or KIRs have been proposed as unique markers of human virtual memory T (TVM) cells, which are T cells featuring memory phenotypes even in neonatal cord blood (63). Human TVM cells express high levels of eomesodermin, CD62L, and CD122; exhibit a CCR7−CD45RA+ TEMRA phenotype; and show increased responsiveness to innate cytokines, such as IL-12, IL-15, and IL-18 (63, 64). However, a recent study demonstrated that CD45RA+CD8+ T cells expressing NKG2A versus KIR are distinct subsets (31). Compared to KIR+CD45RA+CD8+ T cells, NKG2A+CD45RA+CD8+ T cells exhibit downregulated transcripts related to senescence, exhaustion, and regulatory functions. Moreover, the relative proportion of NKG2A+CD45RA+CD8+ T cells declines with age.

    CD8+ T CELLS EXPRESSING NKG2C

    NKG2C also forms a heterodimer with CD94. The NKG2C/CD94 heterodimer binds to HLA-E, similar to NKG2A but with lower affinity, and transduces signals through the immunoreceptor tyrosine activation motif (ITAM)-bearing adaptor molecule DAP12 (65, 66). Like NKG2A, NKG2C is mainly expressed on NK cells, but can also be expressed on some subsets of CD8+ T cells (50, 67). NKG2C+CD8+ T-cell populations have been reported to expand under several pathologic conditions, including CMV infection, Stevens-Johnson syndrome, toxic epidermal necrolysis, and celiac disease (68, 69, 70). Two studies have described NKG2C-mediated CD8+ T-cell activation. Co-stimulation with anti-CD94 and anti-CD3 Abs strengthens the lytic function of NKG2C-expressing CD8+ T cells (50). Even in the absence of TCR stimulation, NKG2C ligation itself can activate T cells to proliferate and kill HLA-E-transfected target cells that do not express the other MHC-I molecules (71). This finding reveals that NKG2C signaling could be a potential alternative to TCR-mediated activation of CD8+ T cells.

    Recent studies have also examined and characterized NKG2C-expressing CD8+ T cells (Fig. 3). One study identified NKG2C as an important marker for potent antimicrobial T cells against Mycobacterium leprae (72). Compared with other CD8+ subsets, CD8+ T cells that express granulysin, perforin, and granzyme B exert superior effector functions against M. leprae-infected macrophages, and these cells typically express NKG2C. Functionally, anti-CD94 Ab enhances the release of cytotoxic molecules from anti-CD3-stimulated NKG2C+CD8+ T cells.

    Figure 3
    Characteristics of CD8+ T cells expressing NKG2C. Balin et al. (72) reported that NKG2C is an important marker for CD8+ T cells expressing granulysin, perforin, and granzyme B (tri-cytotoxic CD8+ T cells), and having greater antimicrobial activity against Mycobacterium leprae. NKG2C ligation activates tri-cytotoxic CD8+ T cells to release cytotoxic proteins. Sottile et al. (67) described downregulation of BCL11B in NKG2C+CD8+ T cells. The loss of BCL11B triggers NK-cell-like reprogramming and induces the generation of NKG2C+CD8+ T cells. Sullivan et al. (38) reported that HLA-E-restricted CD8+ T cells with a TRBV14 repertoire have a low affinity for HLA-E/UL 40 complexes, and express high levels of NKG2C. NKG2C ligation increases the production of IFN-γ and TNF-α from these CD8+ T cells, indicating that NKG2C can compensate for a weak TCR signal.

    HLA-E serves as a ligand of both CD94/NKG2C and CD94/NKG2A, complexed with peptides derived from the leader sequence of classical MHC-I (73). In CMV infection, CMV-encoded UL40, which mimics the leader sequence of classical MHC-I, enables CMV-infected cells to evade NK cell-mediated immune responses by engaging NKG2A (74). On the other hand, NKG2C on NK cells can recognize the HLA-E/UL40 complex, and NKG2C+ NK cells exert cytotoxic functions against CMV-infected cells (75). Furthermore, these NKG2C+ NK cells undergo clonal-like expansion against UL40, similar to the memory response of CD8+ T cells. The NKG2C+CD8+ T-cell population also expands in CMV-infected patients (76). Sottile et al. revealed a mechanism for CD8+ T-cell expansion and reprogramming in CMV-infected patients (67). Bulk RNA-sequencing analysis of the NKG2C+CD8+ T-cell population revealed downregulation of BCL11B. The loss of BCL11B triggers NK-cell-like reprogramming of T cells, and induces the generation of NKG2C+CD8+ T cells under HLA-E ligand stimulation. Additionally, TCR analysis reveals that most NKG2C+CD8+ T cells in CMV-seropositive individuals exhibit narrow TCR Vβ-chain usage, mainly TRBV-14, while NKG2C+CD8+ T cells in CMV-seronegative individuals are more polyclonal. This restricted TCR diversity in CMV-seropositive donors indicates that NKG2C+CD8+ T cells undergo clonal expansion.

    HLA-E is recognized not only by NKG2A and NKG2C, but also by TCRs of CD8+ T cells that are restricted by HLA-E. HLA-E-restricted CD8+ T cells have been investigated in several diseases, including CMV, HIV, Epstein-Barr virus, Mycobacterium tuberculosis, and Salmonella typhi infection (74, 77, 78). Interestingly, HLA-E-restricted CD8+ T cells reportedly exert regulatory properties in tuberculosis infection by inhibiting the proliferation of CD4+ T cells, and patients with autoimmune type I diabetes exhibit a decreased frequency of HLA-E-restricted CD8+ T cells (79, 80). Sullivan et al. (38) examined whether NKG2C played a role in the activation of HLA-E-restricted CD8+ T cells in CMV infection, and demonstrated that NKG2C on HLA-E-restricted CD8+ T cells could co-stimulate CD8+ T cells by compensating for the relatively weak signal intensity of TCRs.

    CONCLUSION

    In the late 1990s, researchers reported CD56+ T cells (termed “natural T cells”) and demonstrated that this T-cell subpopulation exhibits distinct immunologic features, in terms of the expressions of many NK receptors and innate-like features, compared to their CD56− T-cell counterparts. Since those initial descriptions, there have been sporadic reports of CD8+ T-cell populations expressing various NK receptors (Table 1). Some act as co-stimulatory or inhibitory molecules, while others stimulate CD8+ T cells to exert effector functions in a TCR-independent manner. Recent breakthrough technical developments in multi-omics analysis have enabled us to explore the heterogenous subpopulations of CD8+ T cells expressing NK receptors, and to reveal the unique immunologic characteristics of these populations (16, 37). The CD8+ T-cell populations expressing NK receptors execute unique functional roles—for example, regulatory roles—distinct from the conventional CD8+ T-cell population. However, studies have not yet fully clarified the heterogeneity of CD8+ T-cell populations expressing NK receptors. Further studies are needed to delineate the heterogeneity of CD8+ T-cell populations expressing NK receptors, and to elucidate their molecular characteristics and roles in physiologic and pathologic conditions.

    Table 1
    Featured characteristics of human CD8+ T cells expressing NK-associated surface proteins

    Notes

    Conflict of Interest:The authors declare no potential conflicts of interest.

    Author Contributions:

    • Conceptualization: Koh JY, Kim DU, Moon BH, Shin EC.

    • Data curation: Koh JY, Kim DU, Moon BH.

    • Formal analysis: Kim DU, Moon BH.

    • Funding acquisition: Shin EC.

    • Investigation: Koh JY, Kim DU, Moon BH.

    • Methodology: Koh JY, Kim DU, Moon BH.

    • Project administration: Koh JY, Shin EC.

    • Resources: Koh JY.

    • Supervision: Shin EC.

    • Validation: Shin EC.

    • Writing - original draft: Koh JY, Kim DU, Moon BH, Shin EC.

    Abbreviations

    COVID-19 coronavirus disease 2019
    CMV cytomegalovirus
    ITAM immunoreceptor tyrosine activation motif
    ITIM immunoreceptor tyrosine-based inhibitory motif
    KIRs killer cell immunoglobulin-like receptors
    MHC-I MHC class I
    NCAM neural cell adhesion molecule
    SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
    TEMRA effector memory T
    TRM resident memory T
    TVM virtual memory T

    ACKNOWLEDGEMENTS

    This work was supported by the Institute for Basic Science (IBS), Korea, under project code IBS-R801-D2.

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    MeSH Terms
    CD56 Antigen
    CD8-Positive T-Lymphocytes
    Humans*
    Killer Cells, Natural
    NK Cell Lectin-Like Receptor Subfamily C
    Receptors, KIR
    Receptors, Natural Killer Cell
    Respect
    T-Lymphocytes*
    Metrics
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