Human cytolytic T lymphocytes expressing HLA class-I-specific inhibitory receptors
Introduction
MHC class-I-specific inhibitory receptors were first identified in the early 1990s in NK cells both in humans [1, 2, 3, 4] and in mice [5, 6]. iNKRs (inhibitory NK receptors) expressed on NK cells play a major role in enabling the NK cell to discriminate between normal cells (expressing adequate amounts of MHC class I molecules) and cells that have either lost or underexpress MHC class I molecules. Recently, a more complex scenario has emerged; the expression (or lack thereof) of activating receptors on NK cells or their ligands on target cells can also control NK cell activation and function [7, 8•]. The inhibitory receptors in humans include killer immunoglobulin-like receptors (KIRs), leukocyte Ig-like receptors (LIRs) and the CD94–NKG2A heterodimer, which is also present in mice. These receptors have in common the presence of intracytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs) that are required for their inhibitory function [9, 10, 11].
Various cell surface markers and receptors that were initially described in NK cells have also been found in different T cell subsets. In addition, expression of iNKRs can interfere with T cell activation and function or regulate T cell survival upon interaction with their HLA class I ligands.
Although both CD4+ and CD8+ T cell receptor (TCR) αβ+ T cells can express KIRs, KIR+ CD8+ T cells are more prominent [12, 13, 14, 15, 16•, 17•]. NK receptors are also frequently expressed by several ‘nonconventional’ T cell populations, including TCRγδ+ T cells [18], intraepithelial T lymphocytes (T-IELs), and the CD1d-restricted CD4– CD8– or CD4+ CD8– T cells, referred to as NKT cells. In this review we summarize our knowledge of the expression and function of iNKRs on human ‘conventional’ CD8+ cytolytic T lymphocytes (CTLs).
Section snippets
KIRs
The human KIR gene family, which belongs to the immunoglobulin superfamily, contains 15 genes and 2 pseudogenes that are clustered in the leukocyte receptor complex (LRC) on chromosome 19q13.4 [19]. KIRs are type I transmembrane glycoproteins and consist of either two or three immunoglobulin-like domains (designated KIR2D and KIR3D, respectively) in their extracellular region, a transmembrane portion and an intracytoplasmic tail. Notably, the cytoplasmic tail is short (S) in the activating
Phenotypic and functional characteristics of CD8+ TCRαβ+ T cells expressing iNKRs
iNKR+ T cells may be induced ex novo from iNKR− T cells and/or result from expansion of iNKR+ T cells consequent to in vivo T cell responses. In normal donors, KIR+CD8+ T cells are either oligoclonal or, more frequently, monoclonal T cell expansions characterized by different TCR-Vβ rearrangements in different donors [28]. KIR+CD8+ T cells are present in lymph nodes, spleen and tonsils as well as in peripheral blood (PB). However, mature conventional TCRαβ+CD8+ T cells do not express iNKRs
Mechanisms of cell surface expression of iNKRs on CTLs
Various evidence suggests that iNKR expression on T cells occurs during or after activation of fully mature T cells. Thus, iNKR+ T cells bear surface markers that reveal previous activation. T cell clones that share identical rearrangements of TCRα and TCRβ chains can stably express different KIR genes in their clonal progeny, indicating that KIR genes have been transcribed after TCR rearrangement [31, 32]. Recent reports provide evidence that, at least in NK cells, the pattern of KIR
Role of iNKRs in the negative regulation of T-cell activation
Various studies have indicated that the engagement of KIRs, CD94–NKG2A or LIR1 expressed on T cells can result in downregulation of TCR-mediated cell activation [49]. Thus, upon interaction with MHC class I molecules, iNKRs can inhibit T cell effector function (e.g. cytotoxicity and cytokine production). In addition, this has clearly been shown in antigen-specific HLA class I-restricted KIR+CD8+ T lymphocytes [50, 51, 52, 53]. In a recent paper, Guerra et al. [54] investigated the effect of KIR
Conclusions
The surface expression of MHC class-I-specific inhibitory receptors, which are typical of NK cells, on T lymphocytes is an interesting and puzzling finding. Certain iNKR+ T cells that are present in some individuals, were found to be HLA-E-restricted, thus revealing a novel role for HLA-E molecules. The oligo- or monoclonality of these cells, together with their specificity for a limited number of HLA-E-binding peptides, including viral peptides, suggests that they are an additional defence
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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; Ministero dell’Istruzione dell’Università e della Ricerca (MIUR); and Compagnia di San Paolo. We thank Cinzia Miriello and Stefano Canu for secretarial assistance.
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