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1.
J Immunol ; 194(4): 1417-21, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25595774

RESUMO

Triggering receptor expressed on myeloid cells (TREM)-1 is an orphan receptor implicated in innate immune activation. Inhibition of TREM-1 reduces sepsis in mouse models, suggesting a role for it in immune responses triggered by bacteria. However, the absence of an identified ligand has hampered a full understanding of TREM-1 function. We identified complexes between peptidoglycan recognition protein 1 (PGLYRP1) and bacterially derived peptidoglycan that constitute a potent ligand capable of binding TREM-1 and inducing known TREM-1 functions. Interestingly, multimerization of PGLYRP1 bypassed the need for peptidoglycan in TREM-1 activation, demonstrating that the PGLYRP1/TREM-1 axis can be activated in the absence of bacterial products. The role for PGLYRP1 as a TREM-1 activator provides a new mechanism by which bacteria can trigger myeloid cells, linking two known, but previously unrelated, pathways in innate immunity.


Assuntos
Citocinas/imunologia , Imunidade Inata/imunologia , Glicoproteínas de Membrana/imunologia , Neutrófilos/imunologia , Receptores Imunológicos/imunologia , Humanos , Imunoprecipitação , Ligantes , Ressonância de Plasmônio de Superfície , Receptor Gatilho 1 Expresso em Células Mieloides
2.
Clin Immunol ; 134(2): 158-68, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19880352

RESUMO

Natural killer (NK) cells may be protective in HIV infection and are inhibited by killer cell immunoglobulin-like receptors (KIRs) interacting with MHC class I molecules, including HLA-C. Retention of HLA-C despite downregulation of other MHC class I molecules on HIV infected cells might protect infected cells from NK cell recognition in vitro. To assess the role of inhibitory HLA-C ligands in the capacity of NK cells to recognize autologous infected T cells, we measured NK cell degranulation in vitro in viremic patients, controllers with low viremia, and healthy donors. No difference in NK cell response to uninfected compared to HIV-1(IIIB) infected targets was observed. Activation of NK cells was regulated by KIRs, because NK cell degranulation was increased by 1-7F9, a human antibody that binds KIR2DL1/L2/L3 and KIR2DS1/S2, and this effect was most pronounced in KIR haplotype B individuals.


Assuntos
Anticorpos Monoclonais/imunologia , Infecções por HIV/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Receptores KIR/imunologia , Adulto , Feminino , Genótipo , Infecções por HIV/genética , Antígenos HLA-C/genética , Antígenos HLA-C/imunologia , Humanos , Células Jurkat , Células Matadoras Naturais/virologia , Ativação Linfocitária/genética , Masculino , Pessoa de Meia-Idade , Receptores KIR/genética , Viremia
3.
Eur J Immunol ; 40(3): 813-23, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20039300

RESUMO

Missing-self-reactivity can be mimicked by blocking self-specific inhibitory receptors on NK cells, leading to increased rejection of syngeneic tumor cells. Using a mouse model, we investigated whether Ab-mediated blocking of inhibitory receptors, to a degree where NK cells rejected syngeneic tumor cells, would still allow self-tolerance toward normal syngeneic cells. Ly49C/I inhibitory receptors on C57BL/6 (H-2(b)) NK cells were blocked with F(ab')(2) fragments of the mAb 5E6. Inhibitory receptor blockade in vivo caused rejection of i.v. inoculated fluorescence-labeled syngeneic lymphoma line cells but not of syngeneic spleen cells, BM cells or lymphoblasts. The selective rejection of tumor cells was NK cell-dependent and specifically induced by Ly49C/I blockade. Moreover, selective tumor rejection was maintained after treatment with 5E6 F(ab')(2) for 9 wk, arguing against the induction of NK cell anergy or autoreactivity during this time. Combination therapy using 5E6 F(ab')(2) together with high dose IL-2 treatment further increased lymphoma cell rejection. In addition, combination therapy reduced growth of melanoma cell line tumors established by s.c. inoculation 3 days before start of treatment. Our results demonstrate that inhibitory receptor blockade does not result in attack on normal cells, despite potent reactivity against MHC class I-expressing tumors.


Assuntos
Imunoterapia/métodos , Interleucina-2/imunologia , Células Matadoras Naturais/imunologia , Subfamília A de Receptores Semelhantes a Lectina de Células NK/antagonistas & inibidores , Neoplasias Experimentais/imunologia , Tolerância a Antígenos Próprios/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Separação Celular , Citometria de Fluxo , Fragmentos Fab das Imunoglobulinas/imunologia , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Interleucina-2/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Linfoma/terapia , Camundongos , Subfamília A de Receptores Semelhantes a Lectina de Células NK/imunologia , Neoplasias Experimentais/terapia , Tolerância a Antígenos Próprios/efeitos dos fármacos
4.
Proc Natl Acad Sci U S A ; 106(31): 12879-84, 2009 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-19561305

RESUMO

Natural killer (NK) cells are lymphocytes of the innate immune system able to recognize and kill tumors lacking self-MHC class I molecules. This "missing-self" recognition is mediated by the lack of engagement of MHC class I-specific inhibitory NK cell receptors that include the killer cell Ig-like receptors (KIR) in humans and Ly49 molecules in mice. A promising immunotherapeutic strategy against MHC class I(+) cancer cells is to block NK cell inhibitory receptors using monoclonal antibodies (mAb). However, interactions between MHC class I molecules and their inhibitory receptors are also required for the acquisition of NK cell functional competence, a process referred as to "education." In addition, inhibitory receptors are involved in self-tolerance on educated NK cells. Here, we developed a preclinical mouse model in which all NK cells are educated by a single transgenic inhibitory receptor, human KIR2DL3, through the engagement with its HLA-Cw3 ligand. This approach revealed that NK cells could be reprogrammed to control the development of mouse syngenic tumors in vivo. Moreover, in vivo anti-KIR mAb treatment induced the killing of HLA(+) target cells without breaking self-tolerance. Finally, the long-term infusion of anti-KIR mAb neither abolished NK cell education nor tumor cell recognition. Therefore, these results strongly support the use of inhibitory receptor blockade in cancer patients.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos HLA-C/fisiologia , Células Matadoras Naturais/imunologia , Neoplasias Experimentais/terapia , Receptores KIR2DL3/fisiologia , Tolerância a Antígenos Próprios , Animais , Linhagem Celular , Humanos , Imunidade Inata , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia , Receptores KIR2DL3/imunologia
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