NK-CTLs, a novel HLA-E-restricted T-cell subset

doi:10.1016/S1471-4906(03)00031-0

Trends in Immunology

Volume 24, Issue 3, March 2003, Pages 136-143

https://doi.org/10.1016/S1471-4906(03)00031-0 Get rights and content

Abstract

Natural-killer-cytotoxic T lymphocytes (NK-CTLs) are a subset of CD8⁺ CTLs that express HLA (human leukocyte antigen) class I-specific inhibitory receptors. They are detectable in the blood of some individuals as monoclonal expansions and, similar to NK cells, are capable of killing various tumor cell lines. Here, we discuss recent advances that enabled the unraveling of the molecular mechanism by which these cells kill tumors. NK-CTLs, through their T-cell receptor (TCR), recognize HLA-E, a non classical HLA class I molecule characterized by a limited polymorphism and by the ability to bind peptides derived from the leader sequence of various HLA class I alleles as well as from several viral proteins. In addition, NK-CTLs display a broad alloreactivity but spare self cells. In vivo, they are probably generated on recognition of HLA-E-associated viral peptides, undergoing subsequent clonal expansion. Although NK-CTLs might have a role in antiviral defenses, their broad ability to recognize and kill allogeneic cells might pose serious problems in transplantation.

Section snippets

‘NK-like activity’ of NK-CTLs

NK-CTLs represent a small fraction of CD8⁺ TCRαβ cells detectable in the peripheral blood (PB) of some donors. NK-CTLs can be isolated by positive selection on the basis of the coexpression of an iNKR and a given TCRVβ. Surprisingly, they could be highly enriched on mixed lymphocyte culture (MLC) using suitable responder–stimulator combinations [9]. NK-CTL populations and clones, which had been expanded in vitro, displayed a strong cytolytic activity against NK-susceptible tumor cell lines

β₂m-associated surface molecules as possible ligands for the TCR of NK-CTLs

Among the β₂m-associated molecules, the non-classical MHC class I molecules (or MHC class Ib) can be distinguished from classical MHC class I molecules by their limited polymorphism and by their lower levels of expression at the cell surface. In humans, the MHC Ib molecules include HLA-E, -F, -G and -H; in mice, the H-2 complex encodes three non-classical groups of genes represented by the Q, T and M clusters, of which only H2-M3, Qa-1, Qa-2 and T10 have been extensively characterized [2].

NK-CTLs recognize HLA-E

As discussed, among β₂m-associated proteins, HLA-E represents the most suitable ligand for the TCRαβ expressed by NK-CTLs. The evidence that NK-CTLs derived from different donors recognize HLA-E was provided by the analysis of the murine transporter associated with antigen processing-2 (TAP-2)-deficient RMA-S cell line cotransfected with HLA-E and human β₂m. Owing to the lack of TAP-2, RMA-S are unable to transport endogenous peptides from the cytosolic compartment to the endoplasmic reticulum

NK-CTLs display ‘alloreactivity’

A remarkable property of NK-CTLs is the capacity to undergo extensive proliferation in response to allogeneic cells in MLC. Freshly isolated NK-CTLs derived from certain donors are only a small fraction of PB CD8⁺ T lymphocytes, however, on culture in MLC they represent the majority of responding CD8⁺ T lymphocytes (Fig. 1). Although preliminary data would not support this possibility, it cannot be excluded that NK-CTLs could undergo expansion after MLC in vitro from individuals who do not have

Expression and function of iNKRs in NK-CTLs

A typical feature of NK-CTLs is the expression of iNKRs. These include various members of the killer Ig-like receptors (KIRs), such as p58.1 (KIR2DL1), p58.2 (KIR2DL2) and, less frequently, p70 (KIR3DL1) and p140 (KIR3DL2); the CD94–NKG2A heterodimer and LIR1 (ILT2). KIRs recognize allelic determinants expressed on groups of HLA-C, -B or -A alleles 29, 30. However, LIR1 displays a more promiscuous recognition pattern of HLA class I molecules [31], and CD94–NKG2A is specific for HLA-E [13].

NK-CTLs: a novel cell-mediated effector strategy in antimicrobial immunity?

The finding that NK-CTLs recognize HLA-E indicates that this poorly polymorphic non-classical HLA class I molecule represents a novel molecular target for the TCRαβ. Until recent evidence by our and other groups 8, 42, 43, HLA-E was only known as the ligand for CD94–NKG2 receptors, thus mainly confining its role to the regulation of NK-cell function. Because HLA-E actually displays all the features of an antigen-presenting molecule, including the ability to be recognized by T cells, its role in

Alloreactivity and transplantation: the dark side of NK-CTLs

Assuming that NK-CTLs are indeed generated in response to certain viral or bacterial infections, which supply HLA-E-binding peptides, it is conceivable that the broad alloreactivity of NK-CTLs could be the result of crossreactivity between microbial and HLA class I-derived peptides (e.g. the identity between gpUL40_15–23 and HLA Cw^∗0304_3–11 peptides) (Fig. 4). If this holds true, we can speculate that NK-CTLs could have a (unwanted) role in allogeneic transplantation. Indeed, it is conceivable

Concluding remarks

Although the ability to kill tumors was the first function to be recognized for NK-CTLs, it is conceivable that this property might have only a marginal physiological role. NK-CTLs lyse several tumor cell lines, characterized by a general downregulation of classical HLA class I surface expression. In these tumors, the levels of HLA class I molecules are not sufficient to effectively engage iNKRs expressed by NK-CTLs but provide sufficient amounts of peptides enabling HLA-E surface expression

Acknowledgements

This work was supported by grants awarded by Associazione Italiana per la Ricerca sul Cancro (AIRC), Istituto Superiore di Sanità (ISS), Ministero della Salute, and Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MURST), MURST 5%-CNR Biotechnology program 95/95, Consiglio Nazionale delle Ricerche, Progetto Finalizzato Biotecnologie and Compagnia di San Paolo.

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Trends in Immunology

NK-CTLs, a novel HLA-E-restricted T-cell subset

Abstract

Section snippets

‘NK-like activity’ of NK-CTLs

β2m-associated surface molecules as possible ligands for the TCR of NK-CTLs

NK-CTLs recognize HLA-E

NK-CTLs display ‘alloreactivity’

Expression and function of iNKRs in NK-CTLs

NK-CTLs: a novel cell-mediated effector strategy in antimicrobial immunity?

Alloreactivity and transplantation: the dark side of NK-CTLs

Concluding remarks

Acknowledgements

Curr. Opin. Immunol.

Curr. Opin. Immunol.

Immunol. Today

J. Immunol. Methods

Immunity

Immunity

Microbes Infect.

Adv. Immunol.

Hum. Immunol.

Immunity

Blood

Cell

Trends Immunol.

Trends Immunol.

Degradation of cell proteins and the generation of MHC class I-presented peptides

Annu. Rev. Immunol.

The CD1 system: antigen-presenting molecules for T-cell recognition of lipids and glycolipids

Annu. Rev. Immunol.

Human CD8+ T lymphocyte subsets that express HLA class I-specific inhibitory receptors represent oligoclonally or monoclonally expanded cell populations

Proc. Natl. Acad. Sci. U. S. A.

Cytolytic T lymphocytes displaying natural killer (NK)-like activity: expression of NK-related functional receptors for HLA class I molecules (p58 and CD94) and inhibitory effect on the TCR-mediated target-cell lysis or lymphokine production

Int. Immunol.

The analysis of the natural-killer-like activity of human cytolytic T lymphocytes revealed HLA-E as a novel target for TCR α/β-mediated recognition

Eur. J. Immunol.

Identification of HLA-E-specific alloreactive T lymphocytes: a cell subset that undergoes preferential expansion in mixed lymphocyte culture and displays a broad cytolytic activity against allogeneic cells

Proc. Natl. Acad. Sci. U. S. A.

Activating receptors and coreceptors involved in human natural killer-cell-mediated cytolysis

Annu. Rev. Immunol.

Isolation from human placenta of the IgG transporter. FcRn, and localization to the syncytiotrophoblast: implications for maternal-fetal antibody transport

J. Immunol.

Human cytomegalovirus encodes a glycoprotein homologous to MHC class-I antigens

Nature

HLA-E binds to natural killer-cell receptors CD94/NKG2A, B and C

Nature

HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A

Proc. Natl. Acad. Sci. U. S. A.

Functional characterization of HLA-F and binding of HLA-F tetramers to ILT2 and ILT4 receptors

Eur. J. Immunol.

Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis

Proc. Natl. Acad. Sci. U. S. A.

β₂m-associated surface molecules as possible ligands for the TCR of NK-CTLs

Human CD8⁺ T lymphocyte subsets that express HLA class I-specific inhibitory receptors represent oligoclonally or monoclonally expanded cell populations