RESUMO
Abstract Natural killer (NK) cells and cytomegalovirus have been locked in an evolutionary arms race for millions of years in an attempt to overwhelm each other. Cytomegaloviruses deploy cunning disguises to avoid detection by NK cells. Studies of the mouse model of infection have shown that NK cells deploy multiple mechanisms to deal with mouse cytomegalovirus (MCMV) infection, which involve receptors of the C-lectin type superfamily. Remarkably, these receptors have two additional common features: They map to the same genetic region, known as the NK cell gene complex; and they recognize MHC class I-related structures. While reviewing these attack-counterattack measures, this chapter points to the central role that recognition of the MCMV-infected cells by NK cells plays in host resistance to infection.
Assuntos
Células Matadoras Naturais/imunologia , Muromegalovirus/imunologia , Animais , Antígenos Ly/metabolismo , Evolução Biológica , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Lectinas Tipo C/metabolismo , Ligantes , Camundongos , Mimetismo Molecular , Muromegalovirus/genética , Muromegalovirus/patogenicidade , Subfamília D de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptores Imunológicos/metabolismo , Receptores Semelhantes a Lectina de Células NK , Receptores de Células Matadoras NaturaisRESUMO
Our best teachers in revealing the importance of immune pathways are viruses and cancers that have subverted the most prominent pathways to escape from immune recognition. Viruses and cancer impair antigen presentation by classical MHC class I to escape adaptive immunity. The activating receptor NKG2D and its MHC class I-like ligands are other recently defined innate and adaptive immune pathways exploited by viruses and cancer. This review discusses recent advances in the understanding of how NKG2D, expressed on innate immune cells including natural killer cells, gammadelta+ T cells and macrophages, and adaptive immune cells such as CD8+ T cells, recognize stress-induced, MHC class I-like, self-ligands. Moreover, we describe how viruses and cancer have developed strategies to evade this recognition pathway.
Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Receptores Imunológicos/imunologia , Vírus/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Humanos , Ligantes , Macrófagos/imunologia , Camundongos , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Células Matadoras Naturais , Transdução de Sinais , Proteínas Virais/imunologiaAssuntos
Receptores Imunológicos/química , Receptores Imunológicos/fisiologia , Processamento Alternativo , Sequência de Aminoácidos , Animais , Dissulfetos , Humanos , Ligantes , Camundongos , Modelos Biológicos , Dados de Sequência Molecular , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Fosforilação , Isoformas de Proteínas , Estrutura Terciária de Proteína , RNA/química , Splicing de RNA , Receptores de Células Matadoras Naturais , Homologia de Sequência de Aminoácidos , Distribuição Tecidual , Tirosina/químicaRESUMO
In 1986, Kärre and colleagues reported that natural killer (NK) cells rejected an MHC class I-deficient tumor cell line (RMA-S) but they did not reject the same cell line if it expressed MHC class I (RMA). Based on this observation, they proposed the concept that NK cells provide immune surveillance for "missing self," e.g., they eliminate cells that have lost class I MHC antigens. This seminal observation predicted the existence of inhibitory NK cell receptors for MHC class I. Here, we present evidence that NK cells are able to reject tumors expressing MHC class I if the tumor expresses a ligand for NKG2D. Mock-transfected RMA cells resulted in tumor formation. In contrast, when RMA cells were transfected with the retinoic acid early inducible gene-1 gamma or delta (RAE-1), ligands for the activating receptor NKG2D, the tumors were rejected. The tumor rejection was mediated by NK cells, and not by CD1-restricted NK1.1(+) T cells. No T cell-mediated immunological memory against the parental tumor was generated in the animals that had rejected the RAE-1 transfected tumors, which succumbed to rechallenge with the parental RMA tumor. Therefore, NK cells are able to reject a tumor expressing RAE-1 molecules, despite expression of self MHC class I on the tumor, demonstrating the potential for NK cells to participate in immunity against class I-bearing malignancies.
Assuntos
Células Matadoras Naturais/imunologia , Complexo Principal de Histocompatibilidade , Proteínas de Membrana/genética , Animais , Linfócitos B/imunologia , Feminino , Fragmentos Fc das Imunoglobulinas/imunologia , Memória Imunológica , Depleção Linfocítica , Linfoma/genética , Linfoma/imunologia , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes de Fusão/imunologia , Transfecção , Células Tumorais CultivadasRESUMO
NKG2D is an activating receptor that is expressed on most natural killer (NK) cells, CD8 alphabeta T cells, and gammadelta T cells. Among its ligands is the distant major histocompatibility complex class I homolog MICA, which has no function in antigen presentation but is induced by cellular stress. To extend previous functional evidence, the NKG2D-MICA interaction was studied in isolation. NKG2D homodimers formed stable complexes with monomeric MICA in solution, demonstrating that no other components were required to facilitate this interaction. MICA glycosylation was not essential but enhanced complex formation. Soluble NKG2D also bound to cell surface MICB, which has structural and functional properties similar to those of MICA. Moreover, NKG2D stably interacted with surface molecules encoded by three newly identified cDNA sequences (N2DL-1, -2, and -3), which are identical to the human ULBP proteins and may represent homologs of the mouse retinoic acid-early inducible family of NKG2D ligands. Because of the substantial sequence divergence among these molecules, these results indicated promiscuous modes of receptor binding. Comparison of allelic variants of MICA revealed large differences in NKG2D binding that were associated with a single amino acid substitution at position 129 in the alpha2 domain. Varying affinities of MICA alleles for NKG2D may affect thresholds of NK-cell triggering and T-cell modulation.
Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais/imunologia , Proteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Sequência de Aminoácidos , Antígenos de Superfície/metabolismo , Dimerização , Antígenos de Histocompatibilidade Classe I/química , Humanos , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Ligação Proteica , Receptores de Células Matadoras Naturais , Homologia de Sequência de Aminoácidos , SolubilidadeRESUMO
Several inhibitory and activating receptors involved in natural killer cell activation have been characterized. The increasing knowledge about their ligands, including classical MHC class I molecules, non-classical MHC class I molecules and MHC class I-related molecules, is shedding new light on the targets of innate immune recognition. While classical MHC class I molecules are constitutively expressed, some MHC class I-related (MIC) molecules, however, are stress-induced by ill-defined stimuli. Two families of ligands for the human activating NKG2D receptor have been identified. These are the MIC proteins encoded by two highly polymorphic genes within the MHC class I and the retinoic acid-inducible early gene-1-like (also designated UL16-binding) proteins encoded by genes outside the MHC. For the mouse NKG2D receptor, one family, containing at least five distinct ligands, has been described. A better understanding about how targets signal their distress, which renders them susceptible to natural killer (NK)-cell attack, will help to define the role of NK cells in antimicrobial and antitumor immunity and transplantation.
Assuntos
Células Matadoras Naturais/imunologia , Lectinas Tipo C , Receptores Imunológicos/metabolismo , Animais , Antígenos CD/metabolismo , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Ligantes , Glicoproteínas de Membrana/metabolismo , Camundongos , Subfamília D de Receptores Semelhantes a Lectina de Células NK , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Receptores de Células Matadoras Naturais , Transdução de Sinais , Antígenos HLA-ERESUMO
NKG2D is a potent activating receptor on natural killer cells, T cells, and macrophages. Mouse NKG2D interacts with two cell surface ligands related to class I MHC molecules: RAE1 and H60. We used soluble versions of NKG2D, RAE1, and H60 to characterize their interactions. RAE1 and H60 each bind NKG2D with nanomolar affinities, indicating tighter binding than most cell surface immune interactions, but NKG2D binds to H60 with approximately 25-fold higher affinity than to RAE1. RAE1 and H60 compete directly for occupancy of NKG2D, and, thus, NKG2D can be occupied by only one ligand at a time. The NKG2D-H60 interaction is more temperature dependent and makes greater use of electrostatic interactions than the NKG2D-RAE1 interaction. The distinct thermodynamic profiles provide insights into the different molecular mechanisms of the binding interactions.
Assuntos
Proteínas de Membrana/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Receptores Imunológicos/metabolismo , Animais , Ligação Competitiva , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais , Proteínas de Membrana/genética , Camundongos , Antígenos de Histocompatibilidade Menor/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Ligação Proteica , Receptores Imunológicos/genética , Receptores de Células Matadoras Naturais , Proteínas Recombinantes/metabolismo , Eletricidade Estática , TermodinâmicaRESUMO
DX5 mAb is a useful reagent because it stains NK cells from all mouse strains examined. We have identified the molecule recognized by DX5 mAb by using a retrovirus-mediated expression cloning system. A 5-kb cDNA encoding a protein that is reactive with the DX5 mAb was isolated from a NK cell cDNA library, and this molecule was identical with CD49b (very late Ag-2, alpha(2) integrin). The DX5 mAb reacted with transfectants expressing CD49b, and binding of DX5 to the NK cells and CD49b transfectants was blocked in the presence of other anti-CD49b mAbs. When NK1.1(+) NK cells were cultured with IL-2, they progressively lost reactivity with DX5 mAb as a consequence of cellular proliferation. Cytotoxicity mediated by the DX5(+) NK cells was dramatically higher as compared with DX5(-) NK cells. Therefore, DX5 mAb recognizes CD49b and can be used to define functionally distinct subsets of NK cells.
Assuntos
Anticorpos Monoclonais/metabolismo , Antígenos CD/imunologia , Células Matadoras Naturais/imunologia , Animais , Reações Antígeno-Anticorpo , Antígenos CD/biossíntese , Antígenos CD/genética , Antígenos CD/fisiologia , Linhagem Celular , Células Cultivadas , Células Clonais , Clonagem Molecular/métodos , Testes Imunológicos de Citotoxicidade , Humanos , Hibridomas , Integrina alfa2 , Interleucina-2/farmacologia , Células Jurkat , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos LewRESUMO
NK cells can co-express inhibitory and activating killer Ig-like receptors (KIR) recognizing the same HLA class I ligand. We present evidence from experiments with NK cells expressing both activating (KIR2DS2) and inhibitory (KIR2DL2 and KIR2DL3) receptors that the activating KIR can function without apparent interference from the inhibitory KIR. These studies used CD158b mAb that is equally reactive with KIR2DS2, KIR2DL2 and KIR2DL3. First, we show using plastic-immobilized CD158b mAb that the activating KIR2DS2 is stimulated, resulting in NK cell division and degranulation. Second, we show using soluble CD158b mAb and FcRII (+) P815 cells that high concentrations of CD158b mAb trigger the inhibitory KIR, whereas low concentrations stimulate the activating KIR2DS2 resulting in NK cell division and cytolysis. These results demonstrate that the activating KIR2DS2 can function on cells co-expressing the inhibitory KIR2DL2 and/or KIR2DL3, indicating the potential for independent function of activating KIR with natural ligand.
Assuntos
Testes Imunológicos de Citotoxicidade , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos/metabolismo , Receptores Imunológicos/biossíntese , Animais , Anticorpos Monoclonais/metabolismo , Antígenos CD/imunologia , Sítios de Ligação de Anticorpos , Degranulação Celular/imunologia , Divisão Celular/imunologia , Linhagem Celular , Testes Imunológicos de Citotoxicidade/métodos , Humanos , Imunoglobulina G/imunologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Subpopulações de Linfócitos/imunologia , Camundongos , Plásticos/metabolismo , Receptores de IgG/biossíntese , Receptores de IgG/imunologia , Receptores Imunológicos/imunologia , Receptores Imunológicos/fisiologia , Receptores KIR , Receptores KIR2DL2 , Receptores KIR2DL3 , Sarcoma Experimental , Solubilidade , Células Tumorais CultivadasRESUMO
Human leukocyte-associated immunoglobulin-like receptor (LAIR)-1 is expressed on many cells of the immune system and is predicted to mediate inhibitory functions based on the presence of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic domain. Although the role of LAIR-1 in the regulation of immune responses in vivo is unknown, LAIR-1 cross-linking by monoclonal antibody inhibits various immune cell functions in vitro. Here, we identify the colon carcinoma-associated epithelial cellular adhesion molecule (Ep-CAM) as a ligand for LAIR-1 and LAIR-2, a related soluble LAIR-1 family member. Ep-CAM interacts with the LAIR molecules through its first epidermal growth factor domain; Ep-CAM--specific antibodies can abrogate the binding. Intraepithelial T lymphocytes express LAIR-1 and thus may interact with Ep-CAM present on human intestinal epithelium. We propose that LAIR-1--Ep-CAM interaction may contribute to mucosal tolerance and that LAIR-2 possibly modulates this function.
Assuntos
Antígenos de Neoplasias/metabolismo , Moléculas de Adesão Celular/metabolismo , Receptores Imunológicos/metabolismo , Sítios de Ligação , Células Cultivadas , Molécula de Adesão da Célula Epitelial , Células Epiteliais/fisiologia , Humanos , Ligantes , Linfócitos/fisiologia , Estrutura Terciária de Proteína , Receptores Imunológicos/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismoRESUMO
The function of leukocytes is regulated by the integration of positive and negative signals received through cell surface receptors. Related receptors with similar extracellular domains and often binding the same ligands can transmit either inhibitory or activating signals. Studies are beginning to reveal how these 'paired receptors' control immune functions.
Assuntos
Regulação para Baixo/imunologia , Ativação Linfocitária/imunologia , Linfócitos/metabolismo , Receptores Imunológicos/fisiologia , Regulação para Cima/imunologia , Animais , Humanos , Linfócitos/imunologia , Transdução de Sinais/imunologiaRESUMO
Pig immunoreceptor DAP10 cDNA was cloned from a peripheral blood lymphocyte (PBL) cDNA library using human DAP10 cDNA as a probe. The length of the pig DAP10 cDNA is 465 bp and it contains an open reading frame of 237 bp. The predicted polypeptide sequence is 79 amino acids, consisting of an 18-amino acid leader, a 16-amino acid extracellular domain, a 24-amino acid transmembrane segment, and a 21-amino acid cytoplasmic domain. The amino acid sequence of pig DAP10 has 68% and 78% sequence identity with human DAP10 and mouse DAP10, respectively. Pig DAP10 has a conserved aspartic acid in the transmembrane domain, two cysteines in the extracellular domain, and a phophatidylinositol-3 kinase-binding site (YxxM) in the cytoplasmic region. Genomic organization reveals that pig DAP10 comprises four exons and three introns. Pig DAP10 and DAP12 are genetically linked on Chromosome (Chr) 6 at 6q21 in opposite transcriptional orientation, separated by 152 bp. In Northern blot analysis, DAP10 transcripts were detected predominantly in lymphohematopoietic tissues. Pig NKG2D cDNA has an open reading frame of 642 bp. Its expected polypeptide sequence is 214 amino acids. Pig NKG2D has 66% sequence identity with human NKG2D and 56% identity with mouse NKG2D. The NKG2D gene maps to pig Chr 5q25. RT-PCR analysis reveals that pig NKG2D transcripts are expressed in PBLs, NK cells, macrophages, and monocytes. When transiently transfected into COS-7 cells, pig NKG2D requires DAP10 for cell surface expression.
Assuntos
Proteínas de Membrana/genética , Receptores Imunológicos/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Células COS , Chlorocebus aethiops , Clonagem Molecular , DNA Complementar , Expressão Gênica , Humanos , Dados de Sequência Molecular , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Receptores de Células Matadoras Naturais , Porco MiniaturaRESUMO
Natural killer T (NKT) cells are a highly conserved subset of T cells that have been shown to play a critical role in suppressing T helper cell type 1-mediated autoimmune diseases and graft versus host disease in an interleukin (IL)-4-dependent manner. Thus, it is important to understand how the development of IL-4- versus interferon (IFN)-gamma-producing NKT cells is regulated. Here, we show that NKT cells from adult blood and those from cord blood undergo massive expansion in cell numbers (500-70,000-fold) during a 4-wk culture with IL-2, IL-7, phytohemagglutinin, anti-CD3, and anti-CD28 mAbs. Unlike adult NKT cells that preferentially produce both IL-4 and IFN-gamma, neonatal NKT cells preferentially produce IL-4 after polyclonal activation. Addition of type 2 dendritic cells (DC2) enhances the development of neonatal NKT cells into IL-4(+)IFN-gamma(-) NKT2 cells, whereas addition of type 1 dendritic cells (DC1) induces polarization towards IL-4(-)IFN-gamma(+) NKT1 cells. Adult NKT cells display limited plasticity for polarization induced by DC1 or DC2. Thus, newly generated NKT cells may possess the potent ability to develop into IL-4(+)IFN-gamma(-) NKT2 cells in response to appropriate stimuli and may thereafter acquire the tendency to produce both IL-4 and IFN-gamma.
Assuntos
Citocinas/metabolismo , Células Dendríticas/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Doenças Autoimunes/etiologia , Antígenos CD28 , Complexo CD3 , Sangue Fetal/citologia , Sangue Fetal/imunologia , Doença Enxerto-Hospedeiro/etiologia , Humanos , Recém-Nascido , Interferon gama/metabolismo , Interleucina-2 , Interleucina-4/metabolismo , Interleucina-7 , Fito-HemaglutininasRESUMO
The presence of a negatively charged residue in the transmembrane domain of DAP12 precludes its cell surface expression in the absence of a partner receptor containing a positive charge in its transmembrane domain. We utilized this property of DAP12 to screen a BALB / c macrophage cDNA library for novel molecules that induce cell surface expression of DAP12. By this method, we cloned a cell surface receptor with a single Ig (V) domain, a transmembrane lysine residue, and a short cytoplasmic domain. By homology screening of BALB / c macrophage libraries, we identified a second cDNA for a highly homologous receptor. These receptors appear to be the mouse orthologues of a recently identified human cDNA, TREM-2, so we have designated the receptors as mouse TREM-2a and TREM-2b. By Northern blotting, transcripts for TREM-2 were found in each of three macrophage cell lines but not in a variety of other hematopoietic cell lines. We further demonstrate that TREM-2a is associated with endogenous DAP12 in macrophage cells, and cross-linking of TREM-2a on the surface of macrophages leads to the release of nitric oxide. Our studies define TREM-2 as a receptor family in mouse macrophages and demonstrate the capacity of these receptors to activate macrophage function through DAP12.
Assuntos
Macrófagos/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Animais , Linhagem Celular , Clonagem Molecular , Humanos , Imunoglobulinas/genética , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Óxido Nítrico/biossíntese , Filogenia , Estrutura Terciária de Proteína , RNA Mensageiro/biossíntese , Homologia de Sequência de AminoácidosRESUMO
Although natural killer (NK) cells are known to preferentially kill cells that lack major histocompatibility complex class I antigens, we do not know what signals the attack of these targets. Several membrane receptors have recently been implicated in this process and include molecules with immunoreceptor tyrosine-based activation motifs (ITAM) and motifs that bind phosphoinositide-3 kinase (PI3K). Evidence is emerging that NK cells may use a combination of several receptors and signaling pathways to protect the host against infection and possibly against malignancies.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular , Células Matadoras Naturais/imunologia , Receptores Imunológicos/metabolismo , Animais , Antígenos CD28/metabolismo , Proteínas de Transporte/metabolismo , Humanos , Células Matadoras Naturais/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Modelos Biológicos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Proteína Associada à Molécula de Sinalização da Ativação LinfocitáriaRESUMO
Killer cell Ig-like receptor (KIR) and CD94:NKG2A molecules were first defined as human NK cell receptors (NKR), but now are known to be expressed and to function on subpopulations of T cells. Here the repertoires of KIR and CD94:NKG2A expression by T cells from two donors were examined and compared with their previously defined NK cell repertoires. T cell clones generated from peripheral blood of both donors expressed multiple NKR in different combinations and used the range of receptors expressed by NK cells. In both donors alpha beta T cells less frequently expressed the inhibitory receptors CD94:NKG2A and KIR2DL1 than either gamma delta T cells or NK cells. In contrast to NK cells, not all NKR(+) T cells expressed an inhibitory receptor for autologous HLA class I. This lack of specific inhibitory NKR was especially apparent on alpha beta T cells of one donor. Overall, alpha beta T cells exhibited a distinct pattern of NKR expression different from that of gamma delta T and NK cells, which expressed highly similar NKR repertoires. In one donor, analysis of TCR rearrangement revealed a dominant subset of NKR(+) T cells sharing identical TCR alpha- and beta-chains. Remarkably, among 55 T cell clones sharing the same TCR alpha beta rearrangement 18 different KIR phenotypes were seen, suggesting that KIR expression was initiated subsequently to TCR rearrangement.
Assuntos
Antígenos CD/biossíntese , Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T , Células Matadoras Naturais/metabolismo , Lectinas Tipo C , Glicoproteínas de Membrana/biossíntese , Receptores Imunológicos/biossíntese , Subpopulações de Linfócitos T/metabolismo , Sequência de Aminoácidos , Antígenos CD/genética , Sequência de Bases , Linhagem Celular , Células Clonais , Citometria de Fluxo , Humanos , Imunoglobulinas/genética , Células Matadoras Naturais/imunologia , Glicoproteínas de Membrana/genética , Dados de Sequência Molecular , Subfamília C de Receptores Semelhantes a Lectina de Células NK , Subfamília D de Receptores Semelhantes a Lectina de Células NK , Receptores de Antígenos de Linfócitos T alfa-beta/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T gama-delta/biossíntese , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores Imunológicos/genética , Receptores KIR , Receptores KIR2DL1 , Receptores de Células Matadoras Naturais , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Subpopulações de Linfócitos T/imunologiaRESUMO
The human leukocyte receptor complex (LRC) on chromosome 19q13.4 encodes Ig superfamily receptors expressed on hemopoietic cells. Killer Ig-like receptors (KIR) are expressed in cytotoxic lymphocytes but other LRC molecules (Ig-like transcript(ILT)/leukocyte Ig-like receptor (LIR)) are more ubiquitous. We investigated expression of the ILT2/LIR1 inhibitory receptor compared with the related KIR. Both ILT2/LIR1 and KIR were expressed by peripheral CD8(+) T cells with a memory/effector phenotype. ILT2/LIR1(+) T cells demonstrated diverse TCRBV repertoires in contrast to KIR(+) T cells, while numbers of peripheral ILT2/LIR1(+) T cells were greater than KIR(+) T cells and the majority of ILT2/LIR1(+) T cells did not coexpress KIR. Analysis of CD8(+) T cells with specific HLA class I tetramers confirmed this pattern of expression, indicating differential regulation of LRC gene expression in T lymphocytes. Only a minor proportion of ILT2/LIR1(+) KIR(-) clones survived in vitro cloning, were more susceptible to anti-CD3 or cognate peptide induced cell death than KIR(+) T cells and exhibited lower levels of the Bcl-2 survival molecule. Our results indicate a sequential program of LRC-encoded receptor expression with initial ILT2/LIR1 expression in effector T cells and KIR gene transcription in the minor proportion of expanded clones which survives activation-induced cell death to become long term memory T cells.