Biomedical subjects

Sophie Caillat-Zucman

Publications and source records attributed to Sophie Caillat-Zucman.

At least 19 recordsLinked to original sources

PubMed2026

Levels of circulating kidney injury markers and IL-10 identify non-critically ill patients with COVID-19 at risk of death.

BACKGROUNDAfter identifying 2 immunomarkers of acute injury, KIM-1 and LCN2, in all kidney biopsies from 31 patients with COVID-19 pneumonia and de novo kidney dysfunction, we investigated whether circulating markers of kidney epithelial injury are common in patients with laboratory-confirmed COVID-19 who require oxygen support but do not have critical illness.METHODSWe studied 196 patients admitted to 15 hospitals with moderate to severe pneumonia who were enrolled in 2 independent randomized clinical trials. We measured 41 immune mediators and markers of kidney and endothelial injury in peripheral blood in these patients within 24 hours of randomization.RESULTSWe constructed a generalized linear CORIMUNO model combining serum levels of KIM-1, LCN2, IL-10, and age at hospital admission that showed high discrimination for mortality (derivation cohort: AUC = 0.82, 95% CI: 0.73-0.92; validation cohort: AUC = 0.83, 95% CI: 0.74-0.92). An early rise in circulating kidney injury markers, in the absence of acute kidney injury criteria, was markedly associated with the risk of developing a severe form of COVID-19 and death within 3 months.CONCLUSIONThe CORIMUNO score may be a helpful tool for risk stratification, and for the first time to our knowledge, it identifies the overlooked impact of subclinical kidney injury on pneumonia outcomes.TRIAL REGISTRATIONClinicalTrials.gov NCT04324047, NCT04324073, and NCT04331808.FUNDINGThis research was funded by the French Ministry of Health, Programme Hospitalier de Recherche Clinique (PHRC COVID-19-20-0151, PHRC COVID-19-20-0029), Fondation de l'Assistance Publique Hôpitaux de Paris (Alliance Tous Unis Contre le Virus), Assistance Publique Hôpitaux de Paris, and grants from the Fondation pour la Recherche Médicale (FRM) (REA202010012514) and Agence Nationale de Recherches sur le Sida and emerging infectious diseases (ANRS) (ANRS0147) from the VINTED sponsorship.

Humans↗

PubMed2006

HLA class II influences humoral autoimmunity in patients with type 2 autoimmune hepatitis.

BACKGROUND/AIMS: Type 2 autoimmune hepatitis (AIH) is characterized by the presence of anti-liver kidney microsome (anti-LKM-1) and/or anti-liver cytosol type 1 (anti-LC1) autoantibodies. However, the correlation between these autoantibodies and the genetic background has not been studied. METHODS: Frequencies of HLA class II alleles were compared between the 60 Caucasian children with type 2 AIH and 313 control subjects. The anti-LKM1 antibody reactivity directed against antigenic sites of CYP2D6 was analysed by ELISA. RESULTS: HLA-DQB1 *0201 allele was found to be the primary genetic determinant of susceptibility to type 2 AIH by conferring the highest odd-ratio (OR = 6.4). HLA-DRB1 *03 allele was significantly increased (P < 0.0001) among patients with both anti-LKM1 and anti-LC1 autoantibodies as well as in those with only anti-LC1(+) compared to those with anti-LKM1(+) alone. In contrast, HLA-DRB1 *07 allele was significantly associated (P < 0.0001) with anti-LKM1(+) alone compared to groups with both anti-LKM and anti-LC1 or with LC1+ alone. Children with the DRB1 *07 allele develop anti-LKM1 autoantibodies having a more restricted specificity (2 epitopes) than to those having HLA-DRB1 *03 allele (5 epitopes). CONCLUSIONS: The HLA-DR locus is involved in autoantibody expression, while the DQ locus appears to be a critical determinant for the development of type 2 AIH.

Adolescent↗

PubMed2006

Differences in the frequency and function of HHV8-specific CD8 T cells between asymptomatic HHV8 infection and Kaposi sarcoma.

It is unclear how the immune response controls human herpesvirus 8 (HHV8; also known as Kaposi sarcoma-associated herpesvirus [KSHV]) replication and thereby prevents Kaposi sarcoma (KS). We compared CD8 T-cell responses to HHV8 latent (K12) and lytic (glycoprotein B, ORF6, ORF61, and ORF65) antigens in patients who spontaneously controlled the infection and in patients with posttransplantation, AIDS-related, or classical KS. We found that anti-HHV8 responses were frequent, diverse, and strongly differentiated toward an effector phenotype in patients who controlled the infection. Conversely, HHV8-specific CD8 cells were very rare in patients who progressed to KS, and were not recruited to the tumoral tissue, as visualized by in situ tetramer staining of KS biopsies. Last, HHV8-specific CD8 T cells were observed in a seronegative recipient of an HHV8infected graft who remained persistently aviremic and antibody negative, suggesting that specific cytotoxic T lymphocytes (CTLs) may provide protection from persistent HHV8 infection. These results support the crucial role of cellular immune responses in controlling HHV8 replication, in preventing malignancies in latently infected subjects, and in conferring genuine resistance to persistent infection. They may also have important implications for the design of prophylactic and therapeutic HHV8 vaccines, and for adoptive immunotherapy of KS.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Adulthood-onset celiac disease is associated with intercellular adhesion molecule-1 (ICAM-1) gene polymorphism.

Celiac disease (CD) is a multifactorial T-cell-mediated autoimmune disease characterized by gluten-triggered villous atrophy and malabsorption. Although human leukocyte antigen (HLA) class II genes are strong susceptibility factors, non-HLA genes likely contribute to most of CD predisposition. The intercellular adhesion molecule-1 (ICAM-1) gene is a good candidate for CD predisposition because its encoded protein acts as an adhesion and costimulatory receptor. Two single-base polymorphisms (G/A in exon 4 encoding G241R, and A/G in exon 6 encoding K469E) were analyzed in 180 French Caucasian CD case patients (110 patients diagnosed before the age of 15 and 70 patients after the age of 18), and 212 French Caucasian healthy controls. The R241 allele frequency was increased in CD case patients compared with controls (14.2% vs. 5.4% respectively, p = 0.000015, odds ratio [OR] for the R241 allele = 2.9, 95% confidence intervals [CI] = 1.7-4.8). After stratifying for age of disease onset, the R241 variant mainly conferred predisposition to CD occurring during adulthood (OR = 4.2, 95% CI = 2.3-7.5, Pc = 0.000004 for adulthood-onset CD vs. R = 2.1, 95%, CI = 1.2-3.9, Pc = 0.0047 for childhood-onset CD). Position 241 of ICAM-1 maps to the binding site for the integrin Mac-1 and might modify the strength of interaction between endothelium and immune cells. If confirmed in independent datasets, these results may be of importance in at-risk individuals to distinguish rapid from delayed progression to clinical CD.

Adolescent↗

PubMed2006

Clinicopathological significance of major histocompatibility complex class I-related chain a and B expression in thyroid cancer.

CONTEXT: Major histocompatibility complex class I-related chains A and B (MICA/B) are two stress-inducible ligands for the immunoreceptor NKG2D that is expressed on cytotoxic T cells and natural killer (NK) cells. It is not known whether MICA/B expression is up-regulated in thyroid cancer as a result of oncogene activation. OBJECTIVE: The objective of the investigation was to study MICA/B expression and regulation in thyroid cancer and its role in mediating the cytotoxicity of NK cells. METHODS: MICA/B expression in thyroid cancer was analyzed by immunohistochemical staining. Cell surface MICA/B levels in thyroid tumor cell lines and fresh tumor cells were analyzed by flow cytometric analysis. The susceptibility of thyroid tumor cells to NK cell killing was tested by using (51)Cr release assay. RESULTS: MICA/B was expressed at moderate or high levels in 18 of 39 papillary thyroid carcinomas and four of eight anaplastic thyroid carcinomas. MICA/B expression was confirmed by flow cytometric analysis in three fresh thyroid neoplasms. MICA/B expression was detected in eight of 10 thyroid tumor cell lines and correlated with their sensitivity to killing by the NKG2/D-positive NK-92 cells. Blocking of NKG2D and MICA/B interaction by specific antibodies partially led to the inhibition of NK-92 cell-mediated cytotoxicity. The MAPK inhibitors were able to block MICA/B expression in MRO87 and HeLa cells. Transient transfection of mutant BRAF and RAS oncogenes led to increased MICA/B expression in 293 cells and WRO82 cells. CONCLUSION: MICA/B expression is up-regulated in thyroid cancer, probably due to the activation of the MAPK pathway. MICA/B in thyroid cancer plays an important role in NK-92 cell-mediated cytotoxicity.

Antibodies, Monoclonal↗

PubMed2006

How NKG2D ligands trigger autoimmunity?

The function of NK and CD8 T cells in the elimination of infected, transformed, or stressed cells occurs together with tolerance to self, a property that is essential to prevent autoimmunity. Inappropriate expression of NK receptor ligands, leading to activation of autoreactive effector cells, might therefore trigger or exacerbate autoimmunity. We review here some recent data on the activating receptor NKG2D and its MIC ligand, which are indicative of their detrimental roles in some autoimmune disorders.

Animals↗

PubMed2006

MHC class I chain-related gene a diversity in head and neck squamous cell carcinoma.

Many immune-related genes are located within the human leukocyte antigen (HLA) region on chromosome 6. The MHC class I chain-related gene A (MICA), located centromeric of HLA-B, is involved in the innate and adaptive immune response through activation of NK and T cells. Differences of MICA transmembrane repeat lengths have been associated with diseases and expression is observed on epithelial tumors. Head and neck squamous cell carcinoma (HNSCC) is an epithelial tumor. In the present study we evaluated the MICA repeat length diversity in relation to MICA expression in Dutch HNSCC patients. MICA short tandem repeat analysis indicated a significant decrease in the frequency for the MICA-A9 repeat in patients diagnosed with oral cavity squamous cell carcinoma (SCC) but not in patients with SCC in the hypoharynx, larynx, or oropharynx. Interestingly, the majority of patients expressed MICA as observed with immunohistochemical staining whereas no soluble MICA was detected in patients' sera by enzyme-linked immunosorbent assay. In conclusion, the length of the MICA transmembrane repeats in Dutch HNSCC patients does not influence the MICA expression on tumor cells.

Carcinoma, Squamous Cell↗

PubMed2006

The decreased susceptibility of Bcr/Abl targets to NK cell-mediated lysis in response to imatinib mesylate involves modulation of NKG2D ligands, GM1 expression, and synapse formation.

Chronic myeloid leukemia is a clonal multilineage myeloproliferative disease of stem cell origin characterized by the presence of the Bcr/Abl oncoprotein, a constitutively active tyrosine kinase. In previous studies, we have provided evidence that Bcr/Abl overexpression in leukemic cells increased their susceptibility to NK-mediated lysis by different mechanisms. In the present study, using UT-7/9 cells, a high level Bcr/Abl transfectant of UT-7 cells, we show that the treatment of Bcr/Abl target by imatinib mesylate (IM), a specific Abl tyrosine kinase inhibitor, hampers the formation of the NK/target immunological synapse. The main effect of IM involves an induction of surface GM1 ganglioside on Bcr/Abl transfectants that prevents the redistribution of MHC-related Ag molecules in lipid rafts upon interaction with NK cells. IM also affects cell surface glycosylation of targets, as assessed by binding of specific lectins resulting in the subsequent modulation of their binding to lectin type NK receptor, particularly NKG2D. In addition, we demonstrate that the tyrosine kinase activity repression results in a decrease of MHC-related Ags-A/B and UL-16-binding protein expression on Bcr/Abl transfectants UT-7/9. We show that NKG2D controls the NK-mediated lysis of UT-7/9 cells, and IM treatment inhibits this activating pathway. Taken together, our results show that the high expression of Bcr/Abl in leukemic cells controls the expression of NKG2D receptor ligands and membrane GM1 via a tyrosine kinase-dependent mechanism and that the modulation of these molecules by IM interferes with NK cell recognition and cytolysis of the transfectants.

Antineoplastic Agents↗

PubMed2006

Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection.

CD8 T cell killing of hepatitis C virus (HCV)-infected hepatocytes is thought to contribute to liver damage during chronic HCV infection, whereas the participation of HCV-nonspecific immune cells is unclear. To visualize the spatial relationship of HCV-specific CD8 T cells with parenchymal target cells, and to examine their local functional activity in relation to hepatocellular necrosis and fibrosis, we used HLA tetramers and confocal microscopy in biopsies from 23 HLA-A2 or HLA-B7 patients with chronic HCV infection. Intrahepatic tetramer+ (HCV-specific) CD8 T cells protected from hepatic necroinflammatory disease activity, independently of age, gender, viral load, and viral genotype. Indeed, tetramer+ cells were scattered in the liver within regions of weak fibrosis (low laminin expression) and low hepatocellular apoptosis (TUNEL method), and expressed IL-10 but not IFNgamma. By contrast, tetramer-negative CD8 T cells were associated with active necroinflammatory liver disease, colocalized with strong laminin expression and hepatocellular apoptosis, and expressed more frequently IFNgamma than IL-10. Overall, liver regions harboring HCV-specific CD8 T cells tended to be healthier than areas containing only inflammatory cells of undefined specificity. In conclusion, HCV-specific IL-10-producing CD8 T cells, although not cytotoxic and unable to control viral replication, can attenuate hepatocellular necrosis, liver fibrosis, and inflammation mediated by bystander T cells, and may thus represent antigen-induced regulatory CD8 T cells. Therapeutic modulation of the intrahepatic balance between specific and bystander CD8 T cells might be beneficial in patients with chronic hepatitis C.

Adult↗

PubMed2005

CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner.

Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell-mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling innate antitumor immunity. Our experiments indicate that human T reg cells expressed membrane-bound transforming growth factor (TGF)-beta, which directly inhibited NK cell effector functions and down-regulated NKG2D receptors on the NK cell surface. Adoptive transfer of wild-type T reg cells but not TGF-beta-/- T reg cells into nude mice suppressed NK cell-mediated cytotoxicity, reduced NKG2D receptor expression, and accelerated the growth of tumors that are normally controlled by NK cells. Conversely, the depletion of mouse T reg cells exacerbated NK cell proliferation and cytotoxicity in vivo. Human NK cell-mediated tumor recognition could also be restored by depletion of T reg cells from tumor-infiltrating lymphocytes. These findings support a role for T reg cells in blunting the NK cell arm of the innate immune system.

Animals↗

PubMed2005

Crohn's disease associated CARD15 (NOD2) variants are not involved in the susceptibility to type 1 diabetes.

Three variants in the caspase recruitment domain 15/nucleotide-binding oligomerization domain 2 (CARD15/NOD2) gene have been shown to be associated with Crohn's disease (CD). There is a strong support for shared genetic determinants between various autoimmune and inflammatory diseases. In particular, linkage of type 1 diabetes (T1D) and other autoimmune and inflammatory diseases has been reported on chromosome 16, encompassing the region containing the CARD15 gene. We therefore considered this gene as a good candidate for the T1D locus mapped to this region, and we tested the three CARD15 variants in the susceptibility to T1D in two independent settings: family based association analysis in Scandinavian multiplex families that we previously showed to be linked to this region, and case/control association study in a large cohort of French diabetic patients. We found no evidence for association of these variants with T1D overall, nor in subgroups of patients with or without the major risk genotypes at HLA-DRB1, at insulin (INS), or positive or negative for autoantibodies specific to other autoimmune diseases. Our results do not support a role for CD-associated CARD15 variants in the susceptibility to T1D, and suggest that another gene is responsible for the shared susceptibility between autoimmune and inflammatory diseases mapping to this region.

Case-Control Studies↗

PubMed2005

Interleukin-15 activates human natural killer cells to clear the intestinal protozoan cryptosporidium.

Intracellular protozoans of the genus Cryptosporidium are a major cause of diarrheal illness worldwide, but little is known about the mechanisms that control intestinal infection. We have previously demonstrated interleukin (IL)-15 expression in the intestinal mucosa of seronegative symptomatic volunteers after oral challenge with C. parvum, which suggests a role for IL-15 in the control of acute infection. We hypothesize that IL-15 activates an innate cytolytic cell response that contributes to the clearance of initial C. parvum infection. We report here that IL-15 activates peripheral blood mononuclear cells to lyse Cryptosporidium-infected epithelial cells in a dose-dependent manner. Lysis was due to CD3(-)CD16(+)CD56+ cells (i.e., natural killer [NK] cells). Furthermore, flow cytometry revealed that IL-15 increased expression of the activation receptor NKG2D on NK cells, particularly among the CD16Hi cytolytically active cells. Major histocompatibility complex class I-related molecules A and B (MICA and MICB), ligands for NKG2D, were increased after infection of epithelial cell lines and human ileal tissue. These data suggest that IL-15 has an important role in activating an NK cell-mediated pathway that leads to the elimination of intracellular protozoans from the intestines, which is a previously unrecognized feature of NK cell function.

Animals↗

PubMed2005

Recognition of a subregion of human proinsulin by class I-restricted T cells in type 1 diabetic patients.

Proinsulin is a key autoantigen in type 1 diabetes. Evidence in the mouse has underscored the importance of the insulin B chain region in autoimmunity to pancreatic beta cells. In man, a majority of proteasome cleavage sites are predicted by proteasome cleavage algorithms within this region. To study CD8+ T cell responses to the insulin B chain and adjacent C peptide, we selected 8- to 11-mer peptides according to proteasome cleavage patterns obtained by digestion of two peptides covering proinsulin residues 28 to 64. We studied their binding to purified HLA class I molecules and their recognition by T cells from diabetic patients. Peripheral blood mononuclear cells from 17 of 19 recent-onset and 12 of 13 long-standing type 1 diabetic patients produced IFN-gamma in response to proinsulin peptides as shown by using an ELISPOT assay. In most patients, the response was against several class I-restricted peptides. Nine peptides were recognized within the proinsulin region covering residues 34 to 61. Four yielded a high frequency of recognition in HLA-A1 and -B8 patients. Three peptides located in the proinsulin region 41-51 were shown to bind several HLA molecules and to be recognized in a high percentage of diabetic patients.

Adult↗

PubMed2005

BCR/ABL promotes dendritic cell-mediated natural killer cell activation.

BCR/ABL fusion gene, encoding a paradigmatic tyrosine kinase involved in chronic myelogenous leukemia (CML), can modulate the expression of genes involved in natural killer (NK) cell target recognition. Recent reports outline the role of allogeneic antileukemic NK effectors in the graft-versus-leukemia effect but the regulation of NK cell activation in the setting of graft-versus-leukemia effect remains unknown. Here we show that dendritic cells derived from monocytes of CML patients are selectively endowed with NK cell stimulatory capacity in vitro. We further show, using a gene transfer approach in mouse bone marrow progenitors, that ABL/ABL is necessary to promote dendritic cell-mediated NK cell activation. The dendritic cell/NK cell cross-talk in ABL/ABL-induced CML seems unique because JunB or IFN consensus sequence binding protein loss of functions, associated with other myeloproliferative disorders, do not promote dendritic cell-mediated NK cell activation. NK cell activation by leukemic dendritic cells involves NKG2D activating receptors and is blocked by imatinib mesylate. Indeed, ABL/ABL translocation enhances the expression levels of the NKG2D ligands on dendritic cells, which is counteracted by imatinib mesylate. Altogether, the clonal ABL/ABL dendritic cells display the unique and selective ability to activate NK cells and may participate in the NK cell control of CML. This study also highlights the deleterious role of imatinib mesylate at the dendritic cell level for NK cell activation.

Animals↗

PubMed2005

Ex vivo characterization of multiepitopic tumor-specific CD8 T cells in patients with chronic myeloid leukemia: implications for vaccine development and adoptive cellular immunotherapy.

Identification of tumor-associated Ags is a prerequisite for vaccine-based and adoptive immune therapies. Some tumor-associated Ags elicit specific CD8 T cells in patients with chronic myeloid leukemia (CML). Here, we characterized ex vivo responses of CD8 T cells from CML patients to extrajunction bcr-abl peptides and telomerase 540-548 hTert, PR1, and WT1 peptides. CML-specific CD8 T cells were present in most treated patients and were usually multiepitopic: WT1, hTert, PR1, and bcr74 tetramer(+) cells were detected in 85, 82, 67, and 61% of patients, respectively. The breadth and magnitude of these responses did not differ significantly according to treatment or disease status. CML-specific tetramer(+) CD8 T cells had a predominantly memory phenotype, an intermediate perforin content, and low intracellular IFN-gamma accumulation in the presence of the relevant peptide. However, in short-term culture with HLA-matched leukemia cells, the patients' memory T cells were specifically reactivated to become IFN-gamma-producing effector cells, suggesting that CD8 T cell precursors with lytic potential are present in vivo and can be activated by appropriate stimulation. In conclusion, this study shows that multiepitopic tumor-specific CD8 T cell responses occur naturally in most CML patients, opening the way to new strategies for enhancing anti-CML immunity, in particular in patients with minimal residual disease.

Antigens, Neoplasm↗

PubMed2005

Association of the R92Q TNFRSF1A mutation and extracranial deep vein thrombosis in patients with Behçet's disease.

OBJECTIVE: Behçet's disease is a chronic, relapsing, multisystemic inflammatory disorder characterized by recurrent oral and genital ulcers and by ocular, articular, vascular, and central nervous system involvement. The tumor necrosis factor alpha (TNFalpha) pathway is likely involved in the pathophysiology of Behçet's disease. One of the 2 TNFalpha receptors is TNF receptor superfamily 1A (TNFRSF1A). We searched for R92Q TNFRSF1A mutations in patients with Behçet's disease. METHODS: A search for TNFRSF1A mutations was performed by polymerase chain reaction amplification of the TNFRSF1A gene, followed by denaturing high-performance liquid chromatography scanning. RESULTS: Among the 74 unrelated European patients with Behçet's disease, 5 (6.8%) carried the R92Q TNFRSF1A mutation. The frequency of the R92Q mutation in patients with Behçet's disease was significantly higher than that in controls (P = 0.006 by Fisher's exact test). Deep vein thrombosis was significantly associated with the R92Q mutation (P = 0.001 [with Bonferroni adjustment for multiple comparisons]). Among the 30 patients with thrombosis, 10 had cerebral thrombophlebitis. None of these patients had the R92Q mutation. Among the 20 patients with Behçet's disease who had extracranial deep vein thrombosis, 6 had the R92Q mutation, whereas 14 did not (P < 0.0001) CONCLUSION: The R92Q mutation in patients with Behçet's disease is associated with an increased risk of extracranial venous thrombosis. This new finding may help in understanding the complex prothrombotic state in patients with Behçet's disease.

Behcet Syndrome↗

PubMed2004

Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gammac cytokine receptor subunit or JAK-3 deficiency.

Haemopoietic stem-cell transplantation is a life-saving treatment for severe combined immune deficiency. However, there has been little long-term follow-up of this treatment. There is evidence for the persistance of partial immunodeficiency associated with significant infections, including severe human papillomavirus (HPV) disease. We did a retrospective analysis of severe HPV disease in a group of 41 patients with severe combined immune deficiency from one centre who were alive 10 years or longer after haemopoietic stem-cell transplantation. Nine of the 41 patients had extensive chronic HPV disease limited to the skin, with a median onset at 8 years after transplantation. Four had lesions typical of epidermodysplasia verruciformis, a rare genodermatosis. Transplant characteristics, immune status, and chimerism of these nine patients did not differ significantly from those of the other patients. The nine patients with HPV disease had severe combined immune deficiency associated with either common gammac receptor cytokine subunit or Janus kinase-3 (JAK-3) deficiency. By contrast, patients with other forms of severe combined immune deficiency did not have any signs of HPV disease. That genetic causes are the only predisposing factor to be identified for severe combined immune deficiency, suggests that natural-killer cells or gammac/JAK-3-dependent signalling in keratinocytes could have a role in anti-HPV immunity.

Child↗

PubMed2004

Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors.

NKG2D and natural cytotoxicity receptors (NCR) are essential recognition structures that mediate NK cell activation. NKG2D and NCR signaling is achieved through membrane association with signaling adaptors. The adaptors that associate with NCR--such as CD3 zeta, FcR gamma and KARAP/DAP12--bear intracytoplasmic immunoreceptor tyrosine-based activation motifs that activate Syk protein tyrosine kinases. Human NKG2D associates with the DAP10 transmembrane adaptor, which bears a YxxM motif and activates the phosphatidylinositol 3-kinase pathway. In the mouse, a short NKG2D-S isoform, generated by Nkg2d alternative splicing, can associate with either DAP10 or KARAP/DAP12. Here, we report that neither short human NKG2D alternative transcripts nor NKG2D association with KARAP/DAP12 was detected in activated human NK cells. Despite these results, NK cell triggering by both recombinant soluble NKG2D ligands (MICA and ULBP-1) and anti-NCR cross-linking antibodies induced similar CD25 expression, NK cell proliferation and cytokine production. In contrast, NKG2D triggering by anti-NKG2D antibodies did not lead to any detectable activation signals. These data thus show that target recognition via NKG2D or NCR triggers all aspects of NK activation, and pave the way for further dissection of the signaling pathways induced by NK cell recognition of ULBP-1 and MICA.

Adaptor Proteins, Signal Transducing↗