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1.
Eur J Immunol ; 51(8): 2040-2050, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33963550

RESUMO

New ways of characterizing CD8+ memory T cell responses in chronic infections are based on the measurement of chemokine receptor expression (CXCR3, CXCR5, and CX3CR1). We applied these novel phenotyping strategies to chronic HIV infection by comparing healthy donors (HDs), HIV-infected patients receiving antiretroviral therapy (ART), and spontaneous HIV controllers (HICs). In all groups, the memory cells exhibited high proportion of CXCR3+ cells. Proportions of CXCR5+ and CX3CR1+ cells were preferentially observed among central memory cells (Tcm) and effector memory cells (Tem) respectively. Chronic controlled HIV infection impacted the chemokine receptor profile of both HIV-specific and nonspecific CD8+ T cells. In total CD8+ T cells, the proportions of CXCR3- CXCR5- CX3CR1- Tcm and Tem were lower in HIV-infected patients than in HDs with subtle differences between ART and HICs. Such phenotyping strategy also revealed differences in exhaustion and senescence phenotypes, the CXCR3+ CXCR5+ CX3CR1- being more exhausted and senescent than the CXCR3+ CXCR5- CX3CR1- Tcm fraction. Among HIV-specific CD8+ T cells, the vast majority of Tcm cells were CXCR3+ and CXCR5+ cells in contrast with their nonspecific counterparts. In conclusion, the addition of migration markers contributes to better characterize Tcm/Tem compartment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Memória Imunológica/imunologia , Receptores CXCR3/imunologia , Receptores CXCR5/imunologia , Adulto , Feminino , HIV-1/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia
2.
Parasite Immunol ; 42(4): e12702, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020650

RESUMO

AIMS: Schistosomiasis and malaria are endemic in sub-Saharan Africa where Schistosoma haematobium (Sh) and Plasmodium falciparum (Pf) coinfections are thus frequent. We explored the effect of Sh infection on antibody responses directed to Pf merozoite antigens and on malaria susceptibility in Beninese children. METHODS AND RESULTS: A total of 268 children were followed during a malaria transmission season. Detection of Pf infection was performed by microscopy and rapid diagnostic tests. Sh infection was determined in urine by microscopy. Antimalarial antibody, cytokine and HLA-G concentrations were quantified by ELISA. The expression of HLA-G receptors by immune cells was assessed by flow cytometry. Children infected by Sh had higher concentrations of IgG1 directed to MSP3 and GLURPR0 , IgG2 directed to GLURPR0 and IgG3 directed to MSP3, GLURPR0 and GLURPR2 and have lower Pf densities than those uninfected by Sh. No difference in cytokine and HLA-G concentrations was observed between Sh egg carriers and non-carriers. CONCLUSION: Schistosoma haematobium modulates host immune responses directed to Pf antigens. The absence of immune downregulation usually observed during helminth infections is surprising in our study. We hypothesize that the stage of Sh development could partly explain the immune pathways leading to increased antibody levels that favour better control of Pf parasitemia.


Assuntos
Anticorpos Antiprotozoários/sangue , Antimaláricos/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Schistosoma haematobium/imunologia , Esquistossomose Urinária/imunologia , Animais , Antígenos de Protozoários/imunologia , Antimaláricos/uso terapêutico , Benin , Criança , Pré-Escolar , Coinfecção/parasitologia , Citocinas/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Malária Falciparum/complicações , Masculino , Esquistossomose Urinária/complicações , Esquistossomose Urinária/tratamento farmacológico
3.
Cell Mol Life Sci ; 76(17): 3323-3348, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31055643

RESUMO

Mesenchymal stem cells (MSCs) are isolated from multiple biological tissues-adult bone marrow and adipose tissues and neonatal tissues such as umbilical cord and placenta. In vitro, MSCs show biological features of extensive proliferation ability and multipotency. Moreover, MSCs have trophic, homing/migration and immunosuppression functions that have been demonstrated both in vitro and in vivo. A number of clinical trials are using MSCs for therapeutic interventions in severe degenerative and/or inflammatory diseases, including Crohn's disease and graft-versus-host disease, alone or in combination with other drugs. MSCs are promising for therapeutic applications given the ease in obtaining them, their genetic stability, their poor immunogenicity and their curative properties for tissue repair and immunomodulation. The success of MSC therapy in degenerative and/or inflammatory diseases might depend on the robustness of the biological functions of MSCs, which should be linked to their therapeutic potency. Here, we outline the fundamental and advanced concepts of MSC biological features and underline the biological functions of MSCs in their basic and translational aspects in therapy for degenerative and/or inflammatory diseases.


Assuntos
Células-Tronco Mesenquimais/metabolismo , Tecido Adiposo/citologia , Células da Medula Óssea/citologia , Diferenciação Celular , Terapia Baseada em Transplante de Células e Tecidos , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Terapia de Imunossupressão , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Via de Sinalização Wnt
4.
Immunol Rev ; 273(1): 140-55, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27558333

RESUMO

Neutrophils are the most abundant subset of leukocytes and play a crucial role in the immune responses against the daily pathogen attacks faced by the host. Neutrophils exhibit several functions for fighting microbes, including the release of granules containing highly toxic molecules, the production of reactive oxygen species and inflammatory cytokines as well as NETosis. Therefore, immune responses mediated by neutrophils must be tightly regulated to protect the host from pathogen assaults without inducing detrimental inflammation and tissue damage. There is now compelling evidence showing that neutrophils express various inhibitory receptors that specifically control their functions. Some of these inhibitory receptors are contained in the membrane of granules and rapidly move to the cell surface upon neutrophil stimulation. This fast upregulation of inhibitory receptors is an efficient way to rapidly enhance inhibitory signals and increase the neutrophil activation threshold. However, because of their ability to attenuate the immune responses of neutrophils, the inhibitory receptors are attractive target for pathogens. This review discusses these various aspects with a particular emphasis on the regulation of neutrophil behavior through immunoreceptor tyrosine-based inhibition motif (ITIM)-bearing inhibitory receptors belonging to LILR and SIGLEC multi-gene families in humans and animal models.


Assuntos
Motivo de Inibição do Imunorreceptor Baseado em Tirosina/genética , Neutrófilos/imunologia , Receptores Imunológicos/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Animais , Citocinas/metabolismo , Armadilhas Extracelulares/metabolismo , Humanos , Imunidade Inata , Receptores Imunológicos/genética , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/genética , Transdução de Sinais
5.
Cancer Immunol Immunother ; 68(4): 673-685, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30569204

RESUMO

Many pathogens, ranging from viruses to multicellular parasites, promote expansion of MDSCs, which are myeloid cells that exhibit immunosuppressive features. The roles of MDSCs in infection depend on the class and virulence mechanisms of the pathogen, the stage of the disease, and the pathology associated with the infection. This work compiles evidence supported by functional assays on the roles of different subsets of MDSCs in acute and chronic infections, including pathogen-associated malignancies, and discusses strategies to modulate MDSC dynamics to benefit the host.


Assuntos
Doenças Transmissíveis/etiologia , Doenças Transmissíveis/metabolismo , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Doença Aguda , Animais , Biomarcadores , Doença Crônica , Doenças Transmissíveis/tratamento farmacológico , Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunomodulação , Terapia de Alvo Molecular , Células Supressoras Mieloides/efeitos dos fármacos
6.
Cell Mol Life Sci ; 75(10): 1871-1887, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29134249

RESUMO

Classical dendritic cells (cDCs) play a pivotal role in the early events that tip the immune response toward persistence or viral control. In vitro studies indicate that HIV infection induces the dysregulation of cDCs through binding of the LILRB2 inhibitory receptor to its MHC-I ligands and the strength of this interaction was proposed to drive disease progression. However, the dynamics of the LILRB2/MHC-I inhibitory axis in cDCs during early immune responses against HIV are yet unknown. Here, we show that early HIV-1 infection induces a strong and simultaneous increase of LILRB2 and MHC-I expression on the surface of blood cDCs. We further characterized the early dynamics of LILRB2 and MHC-I expression by showing that SIVmac251 infection of macaques promotes coordinated up-regulation of LILRB2 and MHC-I on cDCs and monocytes/macrophages, from blood and lymph nodes. Orientation towards the LILRB2/MHC-I inhibitory axis starts from the first days of infection and is transiently induced in the entire cDC population in acute phase. Analysis of the factors involved indicates that HIV-1 replication, TLR7/8 triggering, and treatment by IL-10 or type I IFNs increase LILRB2 expression. Finally, enhancement of the LILRB2/MHC-I inhibitory axis is specific to HIV-1 and SIVmac251 infections, as expression of LILRB2 on cDCs decreased in naturally controlled chikungunya virus infection of macaques. Altogether, our data reveal a unique up-regulation of LILRB2 and its MHC-I ligands on cDCs in the early phase of SIV/HIV infection, which may account for immune dysregulation at a critical stage of the anti-viral response.


Assuntos
Células Dendríticas/metabolismo , Infecções por HIV/imunologia , HIV-1 , Antígenos de Histocompatibilidade Classe I/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Adulto , Animais , Células Cultivadas , Células Dendríticas/imunologia , Feminino , Infecções por HIV/metabolismo , Humanos , Macaca fascicularis , Masculino , Pessoa de Meia-Idade , Síndrome de Imunodeficiência Adquirida dos Símios/metabolismo , Vírus da Imunodeficiência Símia , Fatores de Tempo , Adulto Jovem
7.
Eur J Immunol ; 47(12): 2113-2123, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28762530

RESUMO

We and others have demonstrated that adipose tissue is a reservoir for HIV. Evaluation of the mechanisms responsible for viral persistence may lead to ways of reducing these reservoirs. Here, we evaluated the immune characteristics of adipose tissue in HIV-infected patients receiving antiretroviral therapy (ART) and in non-HIV-infected patients. We notably sought to determine whether adipose tissue's intrinsic properties and/or HIV induced alteration of the tissue environment may favour viral persistence. ART-controlled HIV infection was associated with a difference in the CD4/CD8 T-cell ratio and an elevated proportion of Treg cells in subcutaneous adipose tissue. No changes in Th1, Th2 and Th17 cell proportions or activation markers expression on T cell (Ki-67, HLA-DR) could be detected, and the percentage of CD69-expressing resident memory CD4+ T cells was not affected. Overall, our results indicate that adipose-tissue-resident CD4+ T cells are not extensively activated during HIV infection. PD-1 was expressed by a high proportion of tissue-resident memory CD4+ T cells in both HIV-infected patients and non-HIV-infected patients. Our findings suggest that adipose tissue's intrinsic immunomodulatory properties may limit immune activation and thus may strongly contribute to viral persistence.


Assuntos
Tecido Adiposo/imunologia , Linfócitos T CD4-Positivos/imunologia , Microambiente Celular/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Receptor de Morte Celular Programada 1/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Reservatórios de Doenças/virologia , Feminino , Citometria de Fluxo , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo
8.
Biochem Biophys Res Commun ; 487(1): 28-33, 2017 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-28365155

RESUMO

Human Leucocyte Antigen-G (HLA-G) is a non classical major histocompatibility complex (MHC) molecule that through RNA splicing can encode seven isoforms which are membrane bound (-G1, -G2, -G3 and -G4) and soluble (-G5, -G6 and -G7). HLA-G is described as important immune suppressor endogenous molecule to favor maternal-fetal tolerance, transplant survival and tumor immune scape. HLA-G shows low protein variability and a unique structural complexity that is related with the expression of different isoforms followed by biochemical processes, such as, proteolytic cleavage, molecular interactions, and protein ubiquitination. Studies with HLA-G have shown difficult to assess the role of the individual isoforms. Thus, the aim of this work was to obtain a HLA-G6 recombinant form. The results indicated the production of high homogeneous preparations of soluble recombinant HLA-G6 (srHLA-G6) with molecular mass 23,603.76 Da, determined by MALD-TOF/TOF. In addition, native and denatured srHLA-G6 were detected by ELISA, using commercial monoclonal antibodies. Finally, we developed a suitable methodology to express srHLA-G6 that could contribute in structural and functional studies involving specific isoforms.


Assuntos
Antígenos HLA-G/química , Antígenos HLA-G/imunologia , Proteínas Recombinantes/química , Sítios de Ligação , Humanos , Peso Molecular , Ligação Proteica , Solubilidade
9.
PLoS Pathog ; 11(9): e1005153, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26402858

RESUMO

Two of the crucial aspects of human immunodeficiency virus (HIV) infection are (i) viral persistence in reservoirs (precluding viral eradication) and (ii) chronic inflammation (directly associated with all-cause morbidities in antiretroviral therapy (ART)-controlled HIV-infected patients). The objective of the present study was to assess the potential involvement of adipose tissue in these two aspects. Adipose tissue is composed of adipocytes and the stromal vascular fraction (SVF); the latter comprises immune cells such as CD4+ T cells and macrophages (both of which are important target cells for HIV). The inflammatory potential of adipose tissue has been extensively described in the context of obesity. During HIV infection, the inflammatory profile of adipose tissue has been revealed by the occurrence of lipodystrophies (primarily related to ART). Data on the impact of HIV on the SVF (especially in individuals not receiving ART) are scarce. We first analyzed the impact of simian immunodeficiency virus (SIV) infection on abdominal subcutaneous and visceral adipose tissues in SIVmac251 infected macaques and found that both adipocytes and adipose tissue immune cells were affected. The adipocyte density was elevated, and adipose tissue immune cells presented enhanced immune activation and/or inflammatory profiles. We detected cell-associated SIV DNA and RNA in the SVF and in sorted CD4+ T cells and macrophages from adipose tissue. We demonstrated that SVF cells (including CD4+ T cells) are infected in ART-controlled HIV-infected patients. Importantly, the production of HIV RNA was detected by in situ hybridization, and after the in vitro reactivation of sorted CD4+ T cells from adipose tissue. We thus identified adipose tissue as a crucial cofactor in both viral persistence and chronic immune activation/inflammation during HIV infection. These observations open up new therapeutic strategies for limiting the size of the viral reservoir and decreasing low-grade chronic inflammation via the modulation of adipose tissue-related pathways.


Assuntos
Tecido Adiposo/virologia , Reservatórios de Doenças , Infecções por HIV/virologia , HIV/fisiologia , Paniculite/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Idoso , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Células Cultivadas , Técnicas de Cocultura , Feminino , HIV/imunologia , HIV/isolamento & purificação , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Macaca fascicularis , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Macrófagos/virologia , Masculino , Pessoa de Meia-Idade , Paniculite/imunologia , Paniculite/metabolismo , Paniculite/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/isolamento & purificação , Células Estromais/imunologia , Células Estromais/metabolismo , Células Estromais/patologia , Células Estromais/virologia
10.
Clin Infect Dis ; 63(9): 1189-1197, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27470243

RESUMO

BACKGROUND: Human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense can be diagnosed in the early hemolymphatic stage (stage 1 [S1]) or meningoencephalitic stage (stage 2 [S2]). Importantly, individuals harbouring high and specific antibody responses to Tbg antigens but negative parasitology are also diagnosed in the field (seropositive [SERO]). Whereas some develop the disease in the months following their initial diagnosis (SERO/HAT), others remain parasitologically negative for long periods (SERO) and are apparently able to control infection. Human leucocyte antigen (HLA)-G, an immunosuppressive molecule, could play a critical role in this variability of progression between infection and disease. METHODS: Soluble HLA-G (sHLA-G) was measured in plasma for patients in the SERO (n = 65), SERO/HAT (n = 14), or HAT (n = 268) group and in cerebrospinal fluid for patients in S1 (n = 55), early S2 (n = 93), or late S2 (n = 110). Associations between these different statuses and the soluble level or genetic polymorphisms of HLA-G were explored. RESULTS: Plasma sHLA-G levels were significantly higher in HAT (P = 6 × 10-7) and SERO/HAT (P = .007) than SERO patients. No difference was observed between the SERO/HAT and HAT groups. Within the HAT group, specific haplotypes (HG010102 and HG0103) displayed increased frequencies in S1 (P = .013) and late S2 (P = .036), respectively. CONCLUSIONS: These results strongly suggest the involvement of HLA-G in HAT disease progression. Importantly, high plasma sHLA-G levels in SERO patients could be predictive of subsequent disease development and could represent a serological marker to help guide therapeutic decision making. Further studies are necessary to assess the predictive nature of HLA-G and to estimate both sensitivity and specificity.


Assuntos
Antígenos HLA-G/sangue , Tripanossomíase Africana/sangue , Adulto , Biomarcadores/sangue , Progressão da Doença , Feminino , Haplótipos , Humanos , Masculino , Prognóstico , Trypanosoma brucei gambiense , Tripanossomíase Africana/fisiopatologia , Tripanossomíase Africana/prevenção & controle
11.
Malar J ; 15: 78, 2016 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-26862036

RESUMO

BACKGROUND: HLA-G, a non-classical HLA class I antigen, is of crucial interest during pregnancy by inhibiting maternal immune response. Its role during infections is discussed, and it has been described that high levels of soluble HLA-G during childhood increase the risk of malaria. To explore more precisely interactions between soluble HLA-G and malaria, latent class analysis was used to test whether distinct sub-populations of children, each with distinctive soluble HLA-G evolutions may suggest the existence of groups presenting variable malaria susceptibility. METHOD: A study was conducted in Benin from 2010 to 2013 and 165 children were followed from birth to 12 months. Evolution of soluble HLA-G was studied by the latent class method. RESULTS: Three groups of children were identified: one with consistently low levels of soluble HLA-G during follow-up, a second with very high levels and a last intermediate group. In all groups, low birth weight, high number of malaria infections and high exposure to malaria transmission were associated with high level of soluble HLA-G. Placental malaria was not. Presence of soluble HLA-G in cord blood increased the probability of belonging to the highest trajectory. CONCLUSION: These results, together with previous ones, confirm the important role of HLA-G in the individual susceptibility to malaria. Assaying soluble HLA-G at birth could be a good indicator of newborns more fragile and at risk of infections during childhood.


Assuntos
Antígenos HLA-G/metabolismo , Malária/metabolismo , Adolescente , Adulto , Suscetibilidade a Doenças/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Gravidez , Adulto Jovem
12.
Proc Natl Acad Sci U S A ; 110(44): 17957-62, 2013 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-24133137

RESUMO

Neutrophils play a major role in inflammatory responses and immune defense against pathogens. Even though expression of inhibitory receptors has been reported on neutrophils, their role remains poorly defined. Here we show that primary human neutrophils expressed immunoglobulin-like transcript 4 (ILT4) inhibitory receptor and that this expression was induced during differentiation of the myelomonoblast PLB-985 cell line into "neutrophil-like" cells. Functional assays indicated that human leukocyte antigen G, the preferred ligand of ILT4, inhibited the phagocytic function of neutrophils. ILT4 engagement also impaired reactive oxygen species production induced through CD32a and both receptors were found colocalized into neutrophil lipid rafts. Moreover, neutrophil degranulation induced through inflammatory stimuli increased ILT4 expression as a result of the rapid translocation of an intracellular pool to the cell surface. Consequently to this ILT4 up-regulation, the human leukocyte antigen G-mediated inhibition of neutrophil phagocytic function was enhanced. Finally, we found that ILT4 up-regulation induced on healthy donor neutrophils following stimulation was impaired in presence of plasma from patients with sepsis. Similarly, ILT4 up-regulation was inhibited in neutrophils from septic patients. Altogether, our results reveal a unique mechanism of regulation of neutrophil functions through ILT4 and its exocytosis that may have implications in inflammatory disorders.


Assuntos
Exocitose/imunologia , Regulação da Expressão Gênica/imunologia , Glicoproteínas de Membrana/imunologia , Neutrófilos/imunologia , Receptores Imunológicos/imunologia , Explosão Respiratória/imunologia , Apoptose , Citometria de Fluxo , Humanos , Microscopia Confocal , Fagocitose/imunologia , Espécies Reativas de Oxigênio/metabolismo , Sepse/imunologia , Sepse/metabolismo
13.
Int J Cancer ; 135(9): 2107-17, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24623585

RESUMO

Human leukocyte antigen-G (HLA-G) expression by tumors has been evidenced in numerous malignancies in association with poor prognosis and resistance to immunotherapy in humans. Particularly, soluble form of HLA-G was measured at high concentrations in malignant effusions and plasma from cancer patients, and inhibits antitumor immune cells in vitro through interaction with immunoglobulin-like transcript (ILT) receptors. Nevertheless, in vivo study demonstrating that HLA-G secretion by tumor cells allows their escape from immunosurveillance remained to be established. Despite nondescribed murine homolog, direct functional interaction of HLA-G with murine paired immunoglobulin-like receptor (PIR)-B, ortholog of human ILT receptors, enables to investigate its role in vivo. Immunocompetent mice were injected either with syngeneic tumor cells co-expressing HLA-G5, the main soluble HLA-G isoform, and the conformation stabilizer human ß2-microglubulin (hß2m), or with hß2m+ HLA-G5- tumor cells. hß2m expressed at both tumor cell surface acted as a tumor antigen triggering a specific humoral response. Interestingly, although hß2m+ HLA-G5- tumors were rejected, secreted HLA-G5 provided hß2m+ HLA-G5+ tumors a protection against hß2m-elicited immune rejection, enabling such immunogenic tumors to grow similarly to a poorly immunogenic tumor. HLA-G5 tumor expression was associated with local and peripheral immunosuppression, characterized by dampened anti-hß2m B-cell response, quantitative and functional T-and B-cell defects, accumulation of myeloid-derived suppressor cells able to inhibit T-cell proliferation and reduced T- and B-cell tumor infiltrate. Our study provides the first in vivo proof that soluble HLA-G counteracts tumor rejection and reinforces the importance to consider HLA-G as a promising target to optimize current cancer immunotherapies.


Assuntos
Linfócitos B/imunologia , Neoplasias da Mama/imunologia , Antígenos HLA-G/imunologia , Melanoma/imunologia , Monitorização Imunológica , Linfócitos T/imunologia , Evasão Tumoral/imunologia , Animais , Antígenos de Neoplasias , Apoptose , Linfócitos B/metabolismo , Linfócitos B/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Antígenos HLA-G/metabolismo , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Ativação Linfocitária , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/metabolismo , Linfócitos T/patologia , Células Tumorais Cultivadas
14.
Malar J ; 13: 312, 2014 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-25115633

RESUMO

BACKGROUND: The immunosuppressive properties of HLA-G protein can create a tolerogenic environment that may allow Plasmodium falciparum to avoid host immune responses. There are known associations between high levels of circulating soluble HLA-G (sHLA-G) and either parasite or viral infections and it has been suggested that the induction of sHLA-G expression could be a mechanism via which infectious agents subvert host immune defence. The study presented here is the first to investigate the possible association between sHLA-G and malaria or malaria related risk factors in Benin. METHODS: A parasitological and clinical follow-up of 165 mothers and their newborns from delivery through to one year of age was conducted in the Tori Bossito area of southern Benin. Plasma levels of sHLA-G were determined by ELISA in maternal peripheral and cord blood and again in infants' peripheral blood at 3, 6, 9 and 12 months of age. The associations between the levels of sHLA-G and malaria risk factors were investigated through multivariate mixed models. RESULTS: Strong correlations were observed between the maternal and cord plasma concentrations of sHLA-G. In multivariate analyses, high cord plasma levels of sHLA-G were independently associated with (i) low birth weight and (ii) an increased risk of P. falciparum infection in infancy. CONCLUSION: These results show for the first time the possible involvement of sHLA-G in generating immune tolerance during pregnancy-associated malaria. Soluble HLA-G may represent a useful marker of susceptibility to malaria in infants and be associated with the higher susceptibility to infection observed for LBW children.


Assuntos
Suscetibilidade a Doenças , Antígenos HLA-G/sangue , Recém-Nascido de Baixo Peso , Malária Falciparum/epidemiologia , Adolescente , Adulto , Benin/epidemiologia , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Gravidez , Medição de Risco , Adulto Jovem
15.
Proc Natl Acad Sci U S A ; 108(7): 2891-6, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21282653

RESUMO

Organ transplantation represents a unique therapeutic option for irreparable organ dysfunction and rejection of transplants results from a breakdown in operational tolerance. Although endothelial cells (ECs) are the first target in graft rejection following kidney transplantation, their capacity to alloactivate and generate particular T lymphocyte subsets that could intervene in this process remains unknown. By using an experimental model of microvascular endothelium, we demonstrate that, under inflammatory conditions, human ECs induced proliferation of memory CD4(+)CD45RA(-) T cells and selectively amplified proinflammatory Th17 and suppressive CD45RA(-)HLA-DR(+)FoxP3(bright) regulatory CD4(+) T lymphocytes (Tregs). Although HLA-DR expression on resting microvascular ECs was sufficient to induce proliferation of memory CD4(+) T cells, Treg amplification was dependent on the interaction with CD54, highly expressed only under inflammatory conditions. Moreover, expansion of Th17 cells was dependent on IL-6 and STAT-3, and inhibition of either specifically impaired Th17, without altering Treg expansion. Collectively these data reveal that the HLA-DR(+) ECs regulate the local inflammatory allogeneic response, promoting either an IL-6/STAT-3-dependent Th17 response or a contact-CD54-dependent regulatory response according to the cytokine environment. Finally, these data open therapeutic perspectives in human organ transplantation based on targeting the IL-6/STAT-3 pathway and/or promoting CD54 dependent Treg proliferation.


Assuntos
Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Antígenos HLA-DR/metabolismo , Inflamação/imunologia , Linfócitos T Reguladores/citologia , Células Th17/citologia , Proliferação de Células , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/metabolismo , Oligonucleotídeos/genética , Reação em Cadeia da Polimerase , Fator de Transcrição STAT3/metabolismo , Estatísticas não Paramétricas , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
16.
Life Sci Alliance ; 7(11)2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39237366

RESUMO

Intercellular protein-protein interactions (PPIs) have pivotal roles in biological functions and diseases. Membrane proteins are therefore a major class of drug targets. However, studying such intercellular PPIs is challenging because of the properties of membrane proteins. Current methods commonly use purified or modified proteins that are not physiologically relevant and hence might mischaracterize interactions occurring in vivo. Here, we describe Cell-Int: a cell interaction assay for studying plasma membrane PPIs. The interaction signal is measured through conjugate formation between two populations of cells each expressing either a ligand or a receptor. In these settings, membrane proteins are in their native environment thus being physiologically relevant. Cell-Int has been applied to the study of diverse protein partners, and enables to investigate the inhibitory potential of blocking antibodies, as well as the retargeting of fusion proteins for therapeutic development. The assay was also validated for screening applications and could serve as a platform for identifying new protein interactors.


Assuntos
Comunicação Celular , Membrana Celular , Proteínas de Membrana , Ligação Proteica , Mapeamento de Interação de Proteínas , Humanos , Proteínas de Membrana/metabolismo , Mapeamento de Interação de Proteínas/métodos , Membrana Celular/metabolismo , Animais , Células HEK293 , Bioensaio/métodos
17.
Cell Rep ; 43(4): 113994, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38530856

RESUMO

Distinct dendritic cell (DC) subsets play important roles in shaping immune responses. Circulating DC precursors (pre-DCs) are more susceptible to HIV infection in vitro, which may explain the inefficiency of immune responses against HIV. However, the interplay between HIV and pre-DC is not defined in vivo. We identify human pre-DC equivalents in the cynomolgus macaque and then analyze their dynamics during simian immunodeficiency virus (SIV) infection to illustrate a sharp decrease of blood pre-DCs in early SIV infection and accumulation in lymph nodes (LNs), where they neglect to upregulate CD83/CD86 or MHC-II. Additionally, SIV infection attenuates the capacity of stimulated LN pre-DCs to produce IL-12p40. Analysis of HIV cohorts provides correlation between costimulatory molecule expression on pre-DCs and T cell activation in spontaneous HIV controllers. These findings pinpoint certain dynamics and functional changes of pre-DCs during SIV infection, providing a deeper understanding of immune dysregulation mechanisms elicited in people living with HIV.


Assuntos
Células Dendríticas , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Células Dendríticas/imunologia , Vírus da Imunodeficiência Símia/imunologia , Humanos , Linfonodos/imunologia , Linfonodos/patologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Infecções por HIV/sangue , Infecções por HIV/patologia , Macaca fascicularis , Ativação Linfocitária/imunologia
18.
Eur J Immunol ; 42(3): 700-9, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22144141

RESUMO

HLA-G is a non-classical HLA class I molecule with tolerogenic properties and restricted tissue distribution. The expression of HLA-G can be induced by tumors thus providing an efficient way to escape the anti-tumoral immune response. Although lipid rafts regulate diverse immunological mechanisms their relationship with HLA-G remains controversial. Our results show that HLA-G-mediated inhibition of both the interaction between NK and tumor cells, and of intracellular calcium flux in NK cells conjugated to their target cells were independent of lipid raft integrity. In addition, cytotoxicity assays indicated that HLA-G continued to efficiently inhibit NK-cell cytolytic function in several different tumor cells independently of lipid raft integrity. Confocal microscopy with 3D reconstruction combined with biochemical analysis showed that HLA-G was mainly localized outside the lipid rafts of tumor cells after cross-linking with specific antibody and remained excluded from lipid rafts during interaction with the ILT2 inhibitory receptor of NK cells. This study indicates that the inhibitory function of HLA-G is uncoupled from lipid raft organization, further distinguishing HLA-G from classical HLA molecules and providing novel information in the understanding of tumor immune escape mechanism mediated through HLA-G.


Assuntos
Antígenos HLA-G/imunologia , Células Matadoras Naturais/imunologia , Melanoma/imunologia , Microdomínios da Membrana/imunologia , Antígenos CD/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica/imunologia , Citometria de Fluxo , Antígenos HLA-G/genética , Humanos , Células Matadoras Naturais/ultraestrutura , Receptor B1 de Leucócitos Semelhante a Imunoglobulina , Microdomínios da Membrana/ultraestrutura , Microscopia Confocal , Receptores Imunológicos/imunologia , Evasão Tumoral/imunologia , beta-Ciclodextrinas/farmacologia
19.
J Immunol ; 186(4): 2210-8, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21242521

RESUMO

The acquisition by T cells of exogenous ligands originally expressed by APC has been already described. However, reports essentially focused on the outward signaling of acquired ligands and their effects on surroundings cells. We investigated the function of transferred receptors (not ligands) on the T cells that acquired them (not on cells they interact with). We show that inhibitory Ig-like transcript 2 receptors efficiently transfer from monocytes to autologous T cells by trogocytosis and integrate within the plasma membrane of the acquirer T cells. Furthermore, the acquired receptors can access compatible signaling machinery within acquirer T cells and use it to signal and alter the functions of their new host cells. These data are a formal demonstration that a transferred molecule may send signals to its new host cell. We also provide evidence that sensitivity to modulatory molecules can be acquired from other cells and introduce the notion of intercellular transfer of sensitivities.


Assuntos
Antígenos CD/fisiologia , Comunicação Celular/imunologia , Imunização/métodos , Receptores Imunológicos/fisiologia , Transdução de Sinais/imunologia , Antígenos CD/biossíntese , Antígenos CD/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Membrana Celular/imunologia , Membrana Celular/metabolismo , Técnicas de Cocultura , Humanos , Receptor B1 de Leucócitos Semelhante a Imunoglobulina , Ligantes , Ativação Linfocitária/imunologia , Fusão de Membrana/imunologia , Monócitos/imunologia , Monócitos/metabolismo , Ligação Proteica/imunologia , Receptores Imunológicos/biossíntese , Receptores Imunológicos/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
20.
J Exp Med ; 220(7)2023 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-37036425

RESUMO

Macrophages play a central role in tissue homeostasis and host defense. However, the properties of human macrophages in non-diseased tissues remain poorly understood. Here, we characterized human tonsil macrophages and identified three subsets with distinct phenotype, transcriptome, life cycle, and function. CD36hi macrophages were related to monocytes, while CD36lo macrophages showed features of embryonic origin and CD36int macrophages had a mixed profile. scRNA-seq on non-human primate tonsils showed that monocyte recruitment did not pre-exist an immune challenge. Functionally, CD36hi macrophages were specialized for stimulating T follicular helper cells, by producing Activin A. Combining reconstruction of ligand-receptor interactions and functional assays, we identified stromal cell-derived TNF-α as an inducer of Activin A secretion. However, only CD36hi macrophages were primed for Activin A expression, via the activity of IRF1. Our results provide insight into the heterogeneity of human lymphoid organ macrophages and show that tonsil CD36hi macrophage specialization is the result of both intrinsic features and interaction with stromal cells.


Assuntos
Macrófagos , Tonsila Palatina , Animais , Humanos , Macrófagos/metabolismo , Monócitos , Fenótipo , Transcriptoma
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