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1.
J Immunol ; 197(6): 2325-37, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27511735

RESUMO

NK cells play a major role in immune defense against human and murine CMV (MCMV) infection. Although the MCMV genome encodes for MHC class I-homologous decoy ligands for inhibitory NK cell receptors to evade detection, some mouse strains have evolved activating receptors, such as Ly49H, to recognize these ligands and initiate an immune response. In this study, we demonstrate that approximately half of the Ly49H-expressing (Ly49H(+)) NK cells in the spleen and liver of C57BL/6 mice also express the inhibitory NKR-P1B receptor. During MCMV infection, the NKR-P1B(-)Ly49H(+) NK cell subset proliferates to constitute the bulk of the NK cell population. This NK cell subset also confers better protection against MCMV infection compared with the NKR-P1B(+)Ly49H(+) subset. The two populations are composed of cells that differ in their surface expression of receptors such as Ly49C/I and NKG2A/C/E, as well as developmental markers, CD27 and CD11b, and the high-affinity IL-2R (CD25) following infection. Although the NKR-P1B(+) NK cells can produce effector molecules such as IFNs and granzymes, their proliferation is inhibited during infection. A similar phenotype in MCMV-infected Clr-b-deficient mice, which lack the ligand for NKR-P1B, suggests the involvement of ligands other than the host Clr-b. Most interestingly, genetic deficiency of the NKR-P1B, but not Clr-b, results in accelerated virus clearance and recovery from MCMV infection. This study is particularly significant because the mouse NKR-P1B:Clr-b receptor:ligand system represents the closest homolog of the human NKR-P1A:LLT1 system and may have a direct relevance to human CMV infection.


Assuntos
Infecções por Herpesviridae/imunologia , Células Matadoras Naturais/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Animais , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Muromegalovirus/imunologia , Muromegalovirus/fisiologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/deficiência , Subfamília B de Receptores Semelhantes a Lectina de Células NK/genética
2.
J Immunol ; 194(6): 2909-18, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25681346

RESUMO

MHC-I-specific receptors play a vital role in NK cell-mediated "missing-self" recognition, which contributes to NK cell activation. In contrast, MHC-independent NK recognition mechanisms are less well characterized. In this study, we investigated the role of NKR-P1B:Clr-b (Klrb1:Clec2d) interactions in determining the outcome of murine hematopoietic cell transplantation in vivo. Using a competitive transplant assay, we show that Clr-b(-/-) bone marrow (BM) cells were selectively rejected by wild-type B6 recipients, to a similar extent as H-2D(b-/-) MHC-I-deficient BM cells. Selective rejection of Clr-b(-/-) BM cells was mitigated by NK depletion of recipient mice. Competitive rejection of Clr-b(-/-) BM cells also occurred in allogeneic transplant recipients, where it was reversed by selective depletion of NKR-P1B(hi) NK cells, leaving the remaining NKR-P1B(lo) NK subset and MHC-I-dependent missing-self recognition intact. Moreover, competitive rejection of Clr-b(-/-) hematopoietic cells was abrogated in Nkrp1b-deficient recipients, which lack the receptor for Clr-b. Of interest, similar to MHC-I-deficient NK cells, Clr-b(-/-) NK cells were hyporesponsive to both NK1.1 (NKR-P1C)-stimulated and IL-12/18 cytokine-primed IFN-γ production. These findings support a unique and nonredundant role for NKR-P1B:Clr-b interactions in missing-self recognition of normal hematopoietic cells and suggest that optimal BM transplant success relies on MHC-independent tolerance mechanisms. These findings provide a model for human NKR-P1A:LLT1 (KLRB1:CLEC2D) interactions in human hematopoietic cell transplants.


Assuntos
Transplante de Medula Óssea/métodos , Células Matadoras Naturais/imunologia , Lectinas Tipo C/imunologia , Proteínas de Membrana/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Linhagem Celular Tumoral , Citometria de Fluxo , Expressão Gênica/imunologia , Rejeição de Enxerto/genética , Rejeição de Enxerto/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Antígeno de Histocompatibilidade H-2D/genética , Antígeno de Histocompatibilidade H-2D/imunologia , Antígeno de Histocompatibilidade H-2D/metabolismo , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Lectinas Tipo C/deficiência , Lectinas Tipo C/genética , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Subfamília B de Receptores Semelhantes a Lectina de Células NK/deficiência , Subfamília B de Receptores Semelhantes a Lectina de Células NK/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Homólogo
3.
J Immunol ; 181(9): 6140-7, 2008 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-18941204

RESUMO

Uterine NK (uNK) cells are a prominent feature of the uterine mucosa and regulate placentation. NK cell activity is regulated by a balance of activating and inhibitory receptors, however the receptor repertoire of mouse uNK cells is unknown. We describe herein two distinct subsets of CD3(-)CD122(+) NK cells in the mouse uterus (comprising decidua and mesometrial lymphoid aggregate of pregnancy) at mid-gestation: a small subset indistinguishable from peripheral NK cells, and a larger subset that expresses NKp46 and Ly49 receptors, but not NK1.1 or DX5. This larger subset reacts with Dolichus biflores agglutinin, a marker of uNK cells in the mouse, and is adjacent to the invading trophoblast. By multiparametric analysis we show that the phenotype of uNK cells is unique and unprecedented in terms of adhesion, activation, and MHC binding potential. Thus, the Ly49 repertoire and the expression of other differentiation markers strikingly distinguish uNK cells from peripheral NK cells, suggesting that a selection process shapes the receptor repertoire of mouse uNK cells.


Assuntos
Imunofenotipagem , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Receptores Imunológicos/biossíntese , Útero/imunologia , Útero/metabolismo , Animais , Antígenos Ly , Complexo CD3/metabolismo , Decídua/citologia , Decídua/imunologia , Decídua/metabolismo , Feminino , Regulação da Expressão Gênica/imunologia , Integrina alfa2/metabolismo , Subunidade beta de Receptor de Interleucina-2/biossíntese , Subunidade beta de Receptor de Interleucina-2/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Subfamília A de Receptores Semelhantes a Lectina de Células NK/biossíntese , Subfamília A de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília B de Receptores Semelhantes a Lectina de Células NK/deficiência , Gravidez , Receptores Imunológicos/genética , Útero/citologia
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