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1.
Nat Immunol ; 21(10): 1205-1218, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32839608

RESUMO

Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4+ and CD8+ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria-two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8+ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4+ T cell activation following infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Leishmania donovani/fisiologia , Leishmaniose Visceral/imunologia , Malária/imunologia , Proteínas de Membrana/metabolismo , Plasmodium/fisiologia , Animais , Células Cultivadas , Citotoxicidade Imunológica , Modelos Animais de Doenças , Exocitose , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Vesículas Secretórias/metabolismo
3.
J Infect Dis ; 220(1): 163-173, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-30796820

RESUMO

Control of visceral leishmaniasis (VL) caused by Leishmania donovani requires interferon-γ production by CD4+ T cells. In VL patients, antiparasitic CD4+ T-cell responses are ineffective for unknown reasons. In this study, we measured the expression of genes associated with various immune functions in these cells from VL patients and compared them to CD4+ T cells from the same patients after drug treatment and from endemic controls. We found reduced GATA3, RORC, and FOXP3 gene expression in CD4+ T cells of VL patients, associated with reduced Th2, Th17, and FOXP3+CD4+ T regulatory cell frequencies in VL patient blood. Interleukin 2 (IL-2) was an important upstream regulator of CD4+ T cells from VL patients, and functional studies demonstrated the therapeutic potential of IL-2 for improving antiparasitic immunity. Together, these results provide new insights into the characteristics of CD4+ T cells from VL patients that can be used to improve antiparasitic immune responses.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucina-2/imunologia , Leishmaniose Visceral/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Animais , Feminino , Humanos , Interferon gama/imunologia , Leishmania donovani/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Th17/imunologia , Células Th2/imunologia
4.
Immunology ; 156(2): 174-186, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30403401

RESUMO

Genetic variation at HLA-DRB1 is a risk factor for visceral leishmaniasis (VL) caused by Leishmania donovani. The single nucleotide polymorphism rs9271252 upstream of the DRB1 gene provides a perfect tag for protective versus risk HLA-DRB1 four-digit alleles. In addition to the traditional role of the membrane-distal region of HLA class II molecules in antigen presentation and CD4 T-cell activation, the membrane-proximal region mediates 'non-traditional' multi-functional activation, differentiation, or death signals, including in DR-expressing T cells. To understand how HLA-DR contributes to disease pathogenesis, we examined expression at the protein level in circulating myeloid (CD14+ , CD16+ ) and lymphoid (CD4+ , CD8+ , CD19+ ) cells of VL patients (pre- and post-treatment) compared with endemic healthy controls (EHC). Although DR expression is reduced in circulating myeloid cells in active disease relative to EHC and post-treatment groups, expression is enhanced on CD4+  DR+ and CD8+  DR+ T cells consistent with T-cell activation. Cells of all myeloid and lymphoid populations from active cases were refractory to stimulation of DR expression with interferon-γ (IFN-γ). In contrast, all populations except CD19+ B cells from healthy blood bank controls showed enhanced DR expression following IFN-γ stimulation. The rs9271252 genotype did not impact significantly on IFN-γ-activated DR expression in myeloid, B or CD8+ T cells, but CD4+ T cells from healthy individuals homozygous for the risk allele were particularly refractory to activated DR expression. Further analysis of DR expression on subsets of CD4+ T cells regulating VL disease could uncover additional ways in which pleiotropy at HLA DRB1 contributes to disease pathogenesis.


Assuntos
Regulação da Expressão Gênica , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Leishmaniose Visceral/genética , Linfócitos , Células Mieloides , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Alelos , Antígenos CD/genética , Antígenos CD/imunologia , Criança , Pré-Escolar , Feminino , Cadeias HLA-DRB1/imunologia , Homozigoto , Humanos , Lactente , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/patologia , Masculino , Fatores de Risco
5.
Parasite Immunol ; 41(1): e12601, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30402883

RESUMO

AIM: Iron is key ingredient for immunosurveillance and host-pathogen interaction. Intracellular pathogen steals the iron from the host, but how parasite orchestrates iron acquisition and affects immune responses remains controversial. We aimed to study the iron homoeostasis in visceral leishmaniasis (VL) and its influence on immune machinery. METHODS AND RESULTS: This study was performed on purified monocytes and T cells, peripheral blood mononuclear cells and splenic aspirates for transcriptional analyses of iron homoeostasis (hepcidin, DMT1, transferrin receptor, ferroportin) and immune modulations (IFN-γ, HLA-DR, IL-10, iNOS, IL-6). Serum/plasma was used for determination of iron, total/transferrin iron-binding capacity and anti-leishmania antibody titres in cases. We report that VL-induced perturbation in iron homoeostasis may cause immune dysfunctions. VL cases had decreased iron uptake by transferrin-dependent and transferrin-independent routes while elevated hepcidin, degraded sole iron exporter ferroportin. Therefore, it appears that perturbation in iron homoeostasis has essential role in HLA-DR mediated antigen presentation and innate armoury by downregulating iNOS as well as altering IFN-γ, IL-6 and IL-10 profiles. CONCLUSION: The iron homoeostasis by hepcidin can serve as one of the crucial determinants for regulating immune cell signalling; therefore, targeting iron metabolism, specifically hepcidin alone or in combination with agonists, can serve to clear infection.


Assuntos
Hepcidinas/imunologia , Homeostase , Ferro/metabolismo , Leishmaniose Visceral/imunologia , Adulto , Apresentação de Antígeno , Proteínas de Transporte de Cátions/metabolismo , Feminino , Hepcidinas/genética , Humanos , Interleucina-10/metabolismo , Leishmania , Leishmaniose Visceral/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Monócitos/metabolismo , Baço/metabolismo , Transcrição Gênica
6.
Parasite Immunol ; 41(11): e12669, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31494954

RESUMO

CD8+ T-cell function is compromised in chronic diseases such as visceral leishmaniasis (VL). However, little is known about the changes in gene expression that cause CD8+ T-cell dysfunction during VL. We used targeted transcriptional profiling of peripheral blood CD8+ T cells from VL patients pre- and post-anti-parasitic drug treatment, and compared them with the same cell population from healthy endemic controls to assess their activation, differentiation and functional status during disease. We found a predominance of downregulated immune genes in CD8+ T cells from VL patients. However, genes encoding several notable immune checkpoint molecules, including LAG-3, TIM-3 and CTLA-4, cytolytic molecules, such as granzymes A, B and H and perforin, as well as SOCS3, STAT1, JAK2 and JAK3 cytokine signalling genes were found to be increasingly expressed by VL patient CD8+ T cells. Additional studies confirmed increased expression of the inhibitory receptors LAG3 and TIM3 on VL patient CD8+ T cells, thereby identifying these molecules as potential targets to improve antigen-specific CD8+ T-cell responses during disease.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Celular/genética , Imunidade Celular/imunologia , Leishmaniose Visceral/imunologia , Adulto , Antígenos CD/genética , Antígeno CTLA-4/genética , Feminino , Perfilação da Expressão Gênica , Granzimas/biossíntese , Granzimas/genética , Receptor Celular 2 do Vírus da Hepatite A/genética , Humanos , Janus Quinase 2/genética , Janus Quinase 3/genética , Leishmaniose Visceral/parasitologia , Masculino , Perforina/biossíntese , Perforina/genética , Fator de Transcrição STAT1/genética , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína do Gene 3 de Ativação de Linfócitos
7.
PLoS Negl Trop Dis ; 18(2): e0011960, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38408097

RESUMO

BACKGROUND: CD4+ T cells play a central role in control of L. donovani infection, through IFN-γ production required for activation of macrophages and killing of intracellular parasites. Impaired control of parasites can in part be explained by hampered CD4+ T cells effector functions in visceral leishmaniasis (VL) patients. In a recent studies that defined transcriptional signatures for CD4+ T cells from active VL patients, we found that expression of the IL-7 receptor alpha chain (IL-7Rα; CD127) was downregulated, compared to CD4+ T cells from endemic controls (ECs). Since IL-7 signaling is critical for the survival and homeostatic maintenance of CD4+ T cells, we investigated this signaling pathway in VL patients, relative to ECs. METHODS: CD4+ T cells were enriched from peripheral blood collected from VL patients and EC subjects and expression of IL7 and IL7RA mRNA was measured by real time qPCR. IL-7 signaling potential and surface expression of CD127 and CD132 on CD4+ T cell was analyzed by multicolor flow cytometry. Plasma levels of soluble IL-7 and sIL-7Rα were measured by ELISA. RESULT: Transcriptional profiling data sets generated previously from our group showed lower IL7RA mRNA expression in VL CD4+ T cells as compared to EC. A significant reduction was, however not seen when assessing IL7RA mRNA by RT-qPCR. Yet, the levels of soluble IL-7Rα (sIL-7Rα) were reduced in plasma of VL patients compared to ECs. Furthermore, the levels of soluble IL-7 were higher in plasma from VL patients compared to ECs. Interestingly, expression of the IL-7Rα protein was higher on VL patient CD4+ T cells as compared to EC, with activated CD38+ CD4+ T cells showing higher surface expression of IL-7Rα compared to CD38- CD4+ T cells in VL patients. CD4+ T cells from VL patients had higher signaling potential baseline and after stimulation with recombinant human IL-7 (rhIL-7) compared to EC, as measured by phosphorylation of STAT5 (pSTAT5). Interestingly, it was the CD38 negative cells that had the highest level of pSTAT5 in VL patient CD4+ T cells after IL-7 stimulation. Thus, despite unaltered or potentially lowered IL7RA mRNA expression by CD4+ T cells from VL patients, the surface expression of the IL-7Rα was higher compared to EC and increased pSTAT5 was seen following exposure to rhIL-7. Accordingly, IL-7 signaling appears to be functional and even enhanced in VL CD4+ T cells and cannot explain the impaired effector function of VL CD4+ T cells. The enhanced plasma IL-7 may serve as part of homeostatic feedback mechanism regulating IL7RA expression in CD4+ T cells.


Assuntos
Linfócitos T CD4-Positivos , Leishmaniose Visceral , Humanos , Interleucina-7 , Leishmaniose Visceral/parasitologia , Transdução de Sinais , RNA Mensageiro/genética
8.
JCI Insight ; 8(24)2023 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-37917177

RESUMO

Control of visceral leishmaniasis (VL) depends on proinflammatory Th1 cells that activate infected tissue macrophages to kill resident intracellular parasites. However, proinflammatory cytokines produced by Th1 cells can damage tissues and require tight regulation. Th1 cell IL-10 production is an important cell-autologous mechanism to prevent such damage. However, IL-10-producing Th1 (type 1 regulatory; Tr1) cells can also delay control of parasites and the generation of immunity following drug treatment or vaccination. To identify molecules to target in order to alter the balance between Th1 and Tr1 cells for improved antiparasitic immunity, we compared the molecular and phenotypic profiles of Th1 and Tr1 cells in experimental VL caused by Leishmania donovani infection of C57BL/6J mice. We also identified a shared Tr1 cell protozoan signature by comparing the transcriptional profiles of Tr1 cells from mice with experimental VL and malaria. We identified LAG3 as an important coinhibitory receptor in patients with VL and experimental VL, and we reveal tissue-specific heterogeneity of coinhibitory receptor expression by Tr1 cells. We also discovered a role for the transcription factor Pbx1 in suppressing CD4+ T cell cytokine production. This work provides insights into the development and function of CD4+ T cells during protozoan parasitic infections and identifies key immunoregulatory molecules.


Assuntos
Interleucina-10 , Infecções por Protozoários , Células Th1 , Células Th1/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-10/metabolismo , Linfócitos T Reguladores/imunologia , Camundongos Endogâmicos C57BL , Leishmania donovani , Leishmaniose Visceral/imunologia , Fator de Transcrição 1 de Leucemia de Células Pré-B/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/parasitologia , Infecções por Protozoários/imunologia , Humanos , Animais , Camundongos , Proteína do Gene 3 de Ativação de Linfócitos/antagonistas & inibidores , Interferon gama/metabolismo , Ligação Proteica , Regiões Promotoras Genéticas/imunologia , Modelos Animais de Doenças
9.
J Clin Invest ; 133(1)2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36594463

RESUMO

Control of intracellular parasites responsible for malaria requires host IFN-γ+T-bet+CD4+ T cells (Th1 cells) with IL-10 produced by Th1 cells to mitigate the pathology induced by this inflammatory response. However, these IL-10-producing Th1 (induced type I regulatory [Tr1]) cells can also promote parasite persistence or impair immunity to reinfection or vaccination. Here, we identified molecular and phenotypic signatures that distinguished IL-10-Th1 cells from IL-10+Tr1 cells in Plasmodium falciparum-infected people who participated in controlled human malaria infection studies, as well as C57BL/6 mice with experimental malaria caused by P. berghei ANKA. We also identified a conserved Tr1 cell molecular signature shared between patients with malaria, dengue, and graft-versus-host disease. Genetic manipulation of primary human CD4+ T cells showed that the transcription factor cMAF played an important role in the induction of IL-10, while BLIMP-1 promoted the development of human CD4+ T cells expressing multiple coinhibitory receptors. We also describe heterogeneity of Tr1 cell coinhibitory receptor expression that has implications for targeting these molecules for clinical advantage during infection. Overall, this work provides insights into CD4+ T cell development during malaria that offer opportunities for creation of strategies to modulate CD4+ T cell functions and improve antiparasitic immunity.


Assuntos
Malária , Linfócitos T Reguladores , Camundongos , Animais , Humanos , Células Th1 , Interleucina-10 , Camundongos Endogâmicos C57BL , Malária/genética , Linfócitos T CD4-Positivos
10.
Infect Genet Evol ; 98: 105210, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35031509

RESUMO

γδ T cells are thymus derived heterogeneous and unconventional T- lymphocyte expressing TCR γ (V γ9) and TCRδ (Vδ2) chain and play an important role in connecting innate and adaptive armaments of immune response. These cells can recognize wide ranges of antigens even without involvement of major histocompatibility complex and exert their biological functions by cytotoxicity or activating various types of immune cells. In recent past, γδ T cells have emerged as an important player during protozoa infection and rapidly expand after exposure with them. They have also been widely studied in vaccine induced immune response against many bacterial and protozoan infections with improved clinical outcome. In this review, we will discuss the various roles of γδ T cells in immunity against malaria and leishmaniasis, the two important protozoan diseases causing significant mortality and morbidity throughout the world.


Assuntos
Imunidade Inata , Linfócitos Intraepiteliais/imunologia , Leishmaniose/imunologia , Malária/imunologia , Humanos
11.
Clin Transl Immunology ; 11(6): e1396, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35663920

RESUMO

Objectives: There is an urgent need to be able to identify individuals with asymptomatic Leishmania donovani infection, so their risk of progressing to VL and transmitting parasites can be managed. This study examined transcriptional markers expressed by CD4+ T cells that could distinguish asymptomatic individuals from endemic controls and visceral leishmaniasis (VL) patients. Methods: CD4+ T cells were isolated from individuals with asymptomatic L. donovani infection, endemic controls and VL patients. RNA was extracted and RNAseq employed to identify differentially expressed genes. The expression of one gene and its protein product during asymptomatic infection were evaluated. Results: Amphiregulin (AREG) was identified as a distinguishing gene product in CD4+ T cells from individuals with asymptomatic L. donovani infection, compared to VL patients and healthy endemic control individuals. AREG levels in plasma and antigen-stimulated whole-blood assay cell culture supernatants were significantly elevated in asymptomatic individuals, compared to endemic controls and VL patients. Regulatory T (Treg) cells were identified as an important source of AREG amongst CD4+ T-cell subsets in asymptomatic individuals. Conclusion: Increased Treg cell AREG expression was identified in individuals with asymptomatic L. donovani infection, suggesting the presence of an ongoing inflammatory response in these individuals required for controlling infection and that AREG may play an important role in preventing inflammation-induced tissue damage and subsequent disease in asymptomatic individuals.

12.
Cell Rep ; 30(8): 2512-2525.e9, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32101732

RESUMO

Type I interferons (IFNs) play critical roles in anti-viral and anti-tumor immunity. However, they also suppress protective immune responses in some infectious diseases. Here, we identify type I IFNs as major upstream regulators of CD4+ T cells from visceral leishmaniasis (VL) patients. Furthermore, we report that mice deficient in type I IFN signaling have significantly improved control of Leishmania donovani, a causative agent of human VL, associated with enhanced IFNγ but reduced IL-10 production by parasite-specific CD4+ T cells. Importantly, we identify a small-molecule inhibitor that can be used to block type I IFN signaling during established infection and acts synergistically with conventional anti-parasitic drugs to improve parasite clearance and enhance anti-parasitic CD4+ T cell responses in mice and humans. Thus, manipulation of type I IFN signaling is a promising strategy for improving disease outcome in VL patients.


Assuntos
Imunidade/efeitos dos fármacos , Interferon Tipo I/farmacologia , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/parasitologia , Parasitos/imunologia , Anfotericina B/farmacologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Epitopos , Humanos , Inflamação/imunologia , Inflamação/patologia , Interferon gama/farmacologia , Camundongos Endogâmicos C57BL , Nitrilas , Parasitos/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Am J Trop Med Hyg ; 100(4): 816-821, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30793688

RESUMO

B-cells have a spectrum of functions ranging from antibody production to antigen presentation and have additional vital roles in immune mechanisms. There is rudimentary knowledge about the role of B-cells in intracellular infections with contradictory findings. We explored the role of B-cell dysfunctions in visceral leishmaniasis (VL) pathogenesis in terms of the phenotypic and functional properties of B-cells during the course of disease. This study was performed on blood and splenic aspirates (SA) of VL cases pre- and post-treatment. Whole blood was used for flow cytometric studies for determining the profiles of B-cells at different time-points of treatment. Peripheral blood mononuclear cells were used for magnetic purification of B-cells, for transcriptional studies by real-time polymerase chain reaction (RT-PCR). Serum/plasma was used for direct agglutination test for determining parasite-specific antibodies and SA were used for scoring the presence of parasite by microscopic examination. Flow cytometric studies depicted decreased B-cell percentages during the entire course of disease and attainment of exhaustive phenotype with tissue-like memory cell markers, indicative of B-cell dysfunctions in VL. In addition, B-cells had compromised abilities of antigen processing and presentation and altered levels of B-lymphocyte-induced maturation protein-1 (Blimp-1). Blimp-1 expression goes hand in hand with B-cell maturation antigen and transmembrane activator and calcium modulator (TACI) and cyclophilin ligand interactor, suggestive of its role in promoting plasma cell survival and antibody production. Elevated level of VL-specific antibody titre was directly correlated with exhausted phenotype and also with disease severity during VL. This study indicated for impaired B-cell functions during chronic infection which may lead to pathological consequences in human VL.


Assuntos
Subpopulações de Linfócitos B/imunologia , Imunidade Humoral , Leishmaniose Visceral/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/imunologia , Apresentação de Antígeno , Humanos , Índia
15.
Am J Trop Med Hyg ; 97(3): 767-770, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28820688

RESUMO

Visceral leishmaniasis (VL) is a chronic parasitic disease associated with suppressed T cell responses. Although parasites reside intracellularly in macrophages during chronic VL, neutrophils are the first host cell to infiltrate the infection site and phagocytose the parasite. Subsets of neutrophils with unusual characteristics have been documented in human VL, but whether the total neutrophil population is aberrant during disease is not known. Therefore, we examined phenotypic characteristics of unfractionated polymorphonuclear leukocyte (neutrophils) from subjects with active VL, and compared these with neutrophils from healthy controls or subjects who have been treated for VL. The data showed decreased mRNA and diminished amounts of the neutrophil chemoattractant CXCL8 (interleukin [IL]-8), increased IL-10 mRNA and protein, and elevated transcripts encoding arginase-1, which is involved in suppressing T cell responses. Neutrophils from VL subjects showed enhanced capacity to phagocytose Leishmania spp. promastigotes. The results suggest that neutrophils may contribute to immunosuppression in subjects with active VL.


Assuntos
Leishmaniose Visceral/imunologia , Neutrófilos/classificação , Adolescente , Adulto , Criança , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Transcriptoma , Adulto Jovem
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