Elsevier

Human Immunology

Volume 61, Issue 1, January 2000, Pages 44-50
Human Immunology

Original Articles
Expression of HLA class I-specific inhibitory receptors in human cytolytic T lymphocytes: a regulated mechanism that controls T-cell activation and function

https://doi.org/10.1016/S0198-8859(99)00158-5Get rights and content

Abstract

Different families of major histocompatibility complex (MHC)-specific inhibitory receptors (NKRs) play a major role in natural killer (NK) cell function, allowing discrimination between normal cells and cells that do not express adequate amounts of MHC class I antigens. This occurs in most instances as a consequence of viral infection or tumor transformation. In T lymphocytes, expression of NKR is mostly confined to activated CD8+ cytolytic T lymphocytes (CTLs). While NKR expression by CTLs may be viewed as a mechanism preventing damages to normal cells by those CTLs that have acquired NK-like activity, it may also down regulate TCR-mediated T cell activation, thus, impairing CTL functions. The finding that certain cytokines can modulate killer inhibitory receptor expression in CTLs is of major interest and might be instrumental in novel therapeutic approaches aimed at the down regulation of T-cell function in transplantation or autoimmunity.

Introduction

The past decade has witnessed the discovery of a number of novel receptors specific for major histocompatibility complex (MHC) class I molecules (NKRs). Different from T-cell receptors (TCRs), these receptors do not display variability, and deliver inhibitory rather than triggering signals. These receptors were originally identified in natural killer (NK) cells. NK cells are known to kill virally infected or tumor cells while sparing normal cells 1, 2, 3. The ability of NK cells to discriminate between normal and abnormal cells was found to reflect the interaction between their NKRs and the MHC molecules expressed on normal cells. While this interaction leads to the inhibition of NK cell cytotoxicity, failure to express adequate amounts of MHC molecules may render tumor or virus-infected cells susceptible to NK-mediated lysis 4, 5, 6.

The need for off signals to avoid the killing of normal cells implies the existence of on signals. In NK cells, these are delivered by triggering receptors specific for still poorly defined ligands, some of which may be costitutively expressed by both normal and tumor cells 5, 6. In other instances, they may represent stress-inducible ligands, thus, their expression would be confined to abnormal cells [7]. Activating receptors that play a central role in NK cell cytotoxicity have recently been identified and cloned 8, 9, 10, 11.

In humans, MHC class I-specific inhibitory receptors belong to distinct molecular families 5, 12. The first belong to the immunoglobulin (Ig) superfamily, encompassing several members characterized by two or three extracellular Ig-like domains that specifically recognize groups of human leukocyte antigen (HLA)-C (p58) 13, 14, 15, 16, HLA-B (p70) 16, 17, 18, and HLA-A alleles (p140) 19, 20. The second family comprises type II membrane molecules that, in common with the murine MHC class I-specific receptor Ly49A [21], belong to the C-type lectin superfamily. These receptors are composed of CD94 [22] covalently associated with NKG2A molecules. CD94/NKG2A was originally thought to display a less defined allele specificity, although some class I alleles seemed to be efficiently recognized while others were not 23, 24, 25, 26, 27. Recent data indicate that the actual specificity of the receptor complex CD94/NKG2A is for the non-classic HLA-class I molecule HLA-E 28, 29. Since HLA-E is surface expressed only in association with certain HLA-class I alleles encoded by different loci (including HLA-A,-B,-C and -G), CD94/NKG2A operates by sensing the overall expression of HLA-class I molecules at the cell surface 28, 29. Another recently identified surface molecule that functions as a promiscuous receptor for different HLA-class I molecules, including HLA-G, is represented by the LIR-1/ILT-2 molecule 30, 31. Different from CD94/NKG2A, LIR-1 does not recognize HLA-E, but binds directly to the various HLA-class I molecules. Another receptor has recently been described that directly binds to different HLA molecules, as revealed by the use of soluble molecules [32].This receptor termed p49 is related to the p58/p70/p140 family of killer inhibitory receptors (KIRs), although it is different from these KIRs for its structure and tissue distribution. The cytoplasmic tail of p49 is characterized by a single ITIM instead of two, while its transmembrane portion contains the charged amino acid lysine; the transmembrane domain of the other KIRs is composed of non-polar amino acids [32]. p49 is not expressed by peripheral blood NK cells, but appears to be expressed by a substantial proportion of NK cells in the placental decidua [33]. Therefore, NK cells able to sense the overall HLA-class I expression on target cells may, in fact, interact either directly with different HLA-class I alleles, as in the case of LIR-1- or p49-positive NK cells, 30, 31, 32, or indirectly upon binding to HLA-E, which is surface expressed in association with given HLA alleles 28, 29. Recently, studies on NKR have aroused more general interest in immunology because of their newly recognized role in T-cell function. Indeed, these receptors have been found to be expressed on a subset of activated T cells, mostly CD8+, in which they can inhibit TCR-mediated functions [5].

Section snippets

Phenotypic and functional characteristics of human T lymphocytes expressing HLA class I-specific inhibitory receptors

When p58 molecules were first identified by the use of monoclonal antibodies (mAbs), it was found that a small fraction of normal cytolytic T lymphocytes (CTL) of either the TCRα/β or TCRγ/δ phenotype expressed these molecules [13]. After the formal demonstration that p58 molecules functioned as HLA-C-specific KIRs in NK cells [14], it was investigated whether they could also exert inhibition on T-cell functions. Crosslinking of p58 in CTL clones was found to induce partial down regulation of

NKR expression by activated CTLs: a fail-safe mechanism which prevents the NK-like cytotoxicity against normal cells

The expression of NKRs that antagonizes the main function of CTLs may appear worrying, since it could result in less efficient removal of potentially dangerous cells. A possible explanation for the advantage of this phenomenon may be provided by those CTLs that have acquired NK-like activity and would, thus, be deleterious to normal cells if they did not express NKR (see below). The expression of NKR can also be viewed as a regulatory mechanism useful for the fine tuning of TCR-mediated

NKR expression by activated CTLs: inhibition of TCR-mediated functions

While NKR expression may prevent killing of normal cells by CTLs with NK-like activity, the other side of the coin is the inability of these cells to control properly viral infections or tumor growth, at least in the case of target cells expressing MHC-class I molecules. In favor of this possibility are recent data in tumor-bearing [47] or human immunodeficiency virus (HIV)-infected patients [48]. A tumor-specific (HLA-A24-restricted) CTL clone isolated from a melanoma patient expressed p58.2

Cytokine-mediated regulation of the expression of NKR in T cells

The data above underscore the importance of identifing the mechanism(s) leading to the expression of KIRs in T lymphocytes. A first clue towards this aim has been provided by experiments investigating the requirements of NK cell maturation in vitro from CD34+ cells isolated from thymus. NK cell maturation occurred when CD34+ thymic precursors were cultured in the presence of interleukin (IL)-15, and the resulting NK cells expressed CD94/NKG2A as the only detectable NKR [50]. On the basis of

Concluding remarks

In conclusion, the discovery of NKR led to major progresses in immunology, not only because it allowed a better understanding of the mechanisms involved in NK cell (and CTL) function, but also because it led to the identification of novel receptor families with important regulatory functions. Regarding T cells, a precise knowledge of the mechanisms that regulate NKR expression upon activation may be important, especially in situations in which this event may be harmful to the host. In addition,

Acknowledgements

We thank Stefano Canu for skillful secretarial assistance.

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    The study was supported by grants awarded by the Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.), Istituto Superiore di Sanità (I.S.S.), Ministero della Sanità, Ministero dell’Università e della Ricerca Scientifica e Tecnologica (M.U.R.S.T.), and Progetto Finalizzato Biotecnologie awarded by Consiglio Nazionale delle Ricerche.

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