33 research outputs found
The FcyRIIIa/CD16a receptor importance among the activating receptors of Natural Killer (NK) cells : cellular expression and functional responses triggered by its engagement.
Les cellules NK sont capables dâADCC (Antibody Dependent Cytotoxicity) suite Ă lâengagement durĂ©cepteur Fc!RIIIa/CD16a, et de fonctions effectrices directes antivirales et anti-tumorales: câest la«cytotoxicitĂ© naturelle ». Ainsi activĂ©es elles peuvent Ă©galement rĂ©pondre en produisant des cytokines, commelâIFN-!. La dĂ©granulation et la synthĂšse dâIFN-! par les cellules NK observĂ©es aprĂšs engagement du rĂ©cepteurCD16a, dont lâexpression est indĂ©pendante du polymorphisme V158F, ont Ă©tĂ© largement supĂ©rieures Ă cellesobtenues avec les autres rĂ©cepteurs activateurs. Son engagement par les AcMor thĂ©rapeutiques a produit desrĂ©ponses fonctionnelles variables selon lâAcMor, et selon les donneurs de cellules. La perte dâexpression duCD16a membranaire sâest rĂ©vĂ©lĂ© ĂȘtre un marqueur sensible de lâactivation des cellules NK, mĂȘme quand cedernier nâĂ©tait pas engagĂ©. Enfin, lâemploi de dâinhibiteur dâADAM17 (TMI-2 et TIMP3) a permis dâobserverle maintien de lâexpression du CD16a aprĂšs activation cellulaire sans augmenter les rĂ©ponses fonctionnelles.Ce travail souligne la place centrale de lâengagement du CD16a dans lâactivation NK.NK cell can trigger ADCC (Antibody Dependent Cytotoxicity) through the engagement of theFc!RIIIa/CD16a receptor, and « Natural Cytotoxicity » after integration of cellular signals coming from theiractivating and inhibitory receptors. Moreover, activated NK cells produce cytokines such as IFN-!.Engagement by monoclonal antibodies (mAb) of CD16a was strongly more efficient than that of any otheractivating receptor to induce degranulation and IFN-! synthesis. Functional responses depend on thetherapeutic mAb used to engage CD16a and on the donor of NK cells. CD16a down-modulation was a verysensitive marker of NK cell activation, whatever the mean of activation. It was inhibited in the presence ofTMI-2 and TIMP3 (ADAM17 inhibitors), whereas CD16-dependent functional responses were not increased.This work highlighted the major role of the CD16a receptor in the activation of NK cells
RÎle majeur du FcyRIIIa/CD16a parmi les récepteurs activateurs des cellules tueuses naturelles (cellules NK) (etude de son expression et des réponses fonctionnelles induites par son engagement.)
Les cellules NK sont capables d ADCC (Antibody Dependent Cytotoxicity) suite Ă l engagement durĂ©cepteur Fc!RIIIa/CD16a, et de fonctions effectrices directes antivirales et anti-tumorales: c est la cytotoxicitĂ© naturelle . Ainsi activĂ©es elles peuvent Ă©galement rĂ©pondre en produisant des cytokines, commel IFN-!. La dĂ©granulation et la synthĂšse d IFN-! par les cellules NK observĂ©es aprĂšs engagement du rĂ©cepteurCD16a, dont l expression est indĂ©pendante du polymorphisme V158F, ont Ă©tĂ© largement supĂ©rieures Ă cellesobtenues avec les autres rĂ©cepteurs activateurs. Son engagement par les AcMor thĂ©rapeutiques a produit desrĂ©ponses fonctionnelles variables selon l AcMor, et selon les donneurs de cellules. La perte d expression duCD16a membranaire s est rĂ©vĂ©lĂ© ĂȘtre un marqueur sensible de l activation des cellules NK, mĂȘme quand cedernier n Ă©tait pas engagĂ©. Enfin, l emploi de d inhibiteur d ADAM17 (TMI-2 et TIMP3) a permis d observerle maintien de l expression du CD16a aprĂšs activation cellulaire sans augmenter les rĂ©ponses fonctionnelles.Ce travail souligne la place centrale de l engagement du CD16a dans l activation NK.NK cell can trigger ADCC (Antibody Dependent Cytotoxicity) through the engagement of theFc!RIIIa/CD16a receptor, and Natural Cytotoxicity after integration of cellular signals coming from theiractivating and inhibitory receptors. Moreover, activated NK cells produce cytokines such as IFN-!.Engagement by monoclonal antibodies (mAb) of CD16a was strongly more efficient than that of any otheractivating receptor to induce degranulation and IFN-! synthesis. Functional responses depend on thetherapeutic mAb used to engage CD16a and on the donor of NK cells. CD16a down-modulation was a verysensitive marker of NK cell activation, whatever the mean of activation. It was inhibited in the presence ofTMI-2 and TIMP3 (ADAM17 inhibitors), whereas CD16-dependent functional responses were not increased.This work highlighted the major role of the CD16a receptor in the activation of NK cells.TOURS-Bibl.Ă©lectronique (372610011) / SudocSudocFranceF
Fixation préférentielle des anticorps recombinants thérapeutiques sur l'allotype 158V du récepteur FCyRIIIA/CD16A exprime sur les cellules Natural Killer (NK) (influence du polymorphisme 158V/F sur le niveau d'expression du récepteur)
TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF
Gradual Increase of FcÎłRIIIa/CD16a Expression and Shift toward IFN-Îł Secretion during Differentiation of CD56dim Natural Killer Cells
Natural killer (NK) cell effector functions include cytotoxicity and secretion of cytokines such as interferon-Îł (IFN-Îł). The immature CD56bright subset of human NK cells lacks expression of FcÎłRIIIa/CD16a, one of the low-affinity immunoglobulin G receptors, or exhibits low-density expression (CD56brightCD16â/dim) and produces IFN-Îł in response to cytokine stimulation, whereas the mature CD56dimCD16+ subset is the most cytotoxic one. A further differentiation/maturation of the latter subset according to the gradual loss of NKG2A and/or gain of KIR2DL (CD158a and CD158b) has been demonstrated and the ability to produce IFN-Îł in response to activating receptor (AR) co-engagement is gradually acquired during terminal differentiation. In the course of flow cytometry analysis of CD56dim NK cells, we noted a substantial intraindividual heterogeneity of expression of FcÎłRIIIa. FcÎłRIIIa is unique among ARs: it does not require the co-engagement of other ARs to induce substantial cytotoxicity or cytokine synthesis in CD56dim cells. We, therefore, investigated whether individual differentiation/maturation of polyclonal CD56dim NK cells defined by expression of NKG2A/KIR2DL is related to FcÎłRIIIa expression and to the heterogeneity of NK cell responses upon FcÎłRIIIa engagement. When we analyzed unstimulated CD56dim cells by increasing level of FcÎłRIIIa expression, we found that the proportion of the more differentiated CD158a,h+ and/or CD158b,j+ cells and that of the less differentiated NKG2A+ cells gradually increased and decreased, respectively. FcÎłRIIIa engagement by using plate-bound murine anti-CD16 monoclonal antibody (mAb) or rituximab or trastuzumab (two therapeutic mAbs), resulted in donor-dependent partial segregation of IFN-Îł-producing and/or degranulating CD56dim cells. Importantly, the proportion of CD158a,h/b,j+ cells and that of NKG2A+ cells was increased and decreased, respectively, IFN-Îł-producing cells, whereas these proportions were poorly modified in degranulating cells. Similar results were observed after engagement of ARs by a combination of mAbs targeting NKG2D, NKp30, NKp46, and 2B4. Thus, the gradual increase of FcÎłRIIIa expression is an important feature of the differentiation/maturation of CD56dim cells and this differentiation/maturation is associated with a shift in functionality toward IFN-Îł secretion observed upon both FcÎłRIIIa-dependent and FcÎłRIIIa-independent stimulation. The functional heterogeneity related to the differentiation/maturation of CD56dim NK cells could be involved in the variability of the clinical responses observed in patients treated with therapeutic mAbs
FcgRIIIa Expression Is Not Increased on Natural Killer Cells Expressing the FcgRIIIa-158V Allotype.
International audienc
Deleterious impact of feto-maternal MHC compatibility on the success of pregnancy in a macaque model
International audienc
Antibody-dependent cellular cytotoxicity (ADCC) is mediated by genetically modified antigen-specific human T lymphocytes
The oxygen carrier M101 alleviates complement activation, which may be beneficial for donor organ preservation
International audienceDuring organ transplantation, ischemia/reperfusion injury and pre-formed anti-HLA antibodies are the main cause of delayed graft function and recovery through the activation of the complement system. By supplying oxygen during transplantation, M101 is suspected to avoid complement activation, however, a direct effect exerted by M101 on this pathway is unknown. This was tested by using functional assays (lymphocytotoxic crossmatch test, C3d Luminex-based assay, 50% complement hemolysis [CH50], and 50% alternative complement pathway [AP50/AH50]), and quantitative assays (C3, C3a, C4, C5, C5a, C6, C7, C8, C9 and sC5b-9). M101 interferes with the anti-HLA lymphocytotoxic crossmatch assay, and this effect is complement-dependent as M101 inhibits the classical complement pathway (CH50) in a dose-dependent and stable manner. Such inhibition was independent from a proteolytic effect (fractions C3 to C9) but related to a dose-dependent inhibition of the C3 convertase as demonstrated by exploring downstream the release of the anaphylatoxins (C3a and C5a), C3d, and sC5b-9. The C3 convertase inhibition in the presence of M101 was further demonstrated in the AP50/AH50 assay. In conclusion, the use of M101 avoids the activation of the complement pathway, which constitutes an additional advantage for this extracellular hemoglobin to preserve grafts from ischemia/reperfusion injury and preformed anti-HLA antibodies