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1.
Immunology ; 158(2): 104-120, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31318442

RESUMO

Activation of B and T lymphocytes leads to major remodelling of the metabolic landscape of the cells enabling their post-activation functions. However, naive B and T lymphocytes also show metabolic differences, and the genesis, nature and functional significance of these differences are not yet well understood. Here we show that resting B-cells appeared to have lower energy demands than resting T-cells as they consumed lower levels of glucose and fatty acids and produced less ATP. Resting B-cells are more dependent on OXPHOS, while T-cells show more dependence on aerobic glycolysis. However, despite an apparently higher energy demand, T lineage cells showed lower rates of protein synthesis than equivalent B lineage stages. These metabolic differences between the two lineages were established early during lineage differentiation, and were functionally significant. Higher levels of protein synthesis in B-cells were associated with increased synthesis of MHC class II molecules and other proteins associated with antigen internalization, transport and presentation. The combination of higher energy demand and lower protein synthesis in T-cells was consistent with their higher ATP-dependent motility. Our data provide an integrated perspective of the metabolic differences and their functional implications between the B and T lymphocyte lineages.


Assuntos
Linfócitos B/metabolismo , Glicólise/imunologia , Fosforilação Oxidativa , Linfócitos T/metabolismo , Trifosfato de Adenosina/biossíntese , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Ácidos Graxos/metabolismo , Expressão Gênica , Glucose/metabolismo , Glicólise/genética , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Imunofenotipagem , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Especificidade de Órgãos , Cultura Primária de Células , Biossíntese de Proteínas/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia
2.
bioRxiv ; 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38746242

RESUMO

The protein known as PI3K-interacting protein (PIK3IP1), or transmembrane inhibitor of PI3K (TrIP), is highly expressed by T cells and can modulate PI3K activity in these cells. Several studies have also revealed that TrIP is rapidly downregulated following T cell activation. However, it is unclear as to how this downregulation is controlled. Using a novel monoclonal antibody that robustly stains cell-surface TrIP, we demonstrate that TrIP is lost from the surface of activated T cells in a manner dependent on the strength of signaling through the T cell receptor (TCR) and specific downstream signaling pathways. In addition, TrIP expression returns after 24 hours, suggesting that it may play a role in resetting TCR signaling at later time points. Finally, by expressing truncated forms of TrIP in cells, we identify the region in the extracellular stalk domain of TrIP that is targeted for proteolytic cleavage by metalloprotease ADAM17.

3.
Indian J Med Res ; 138(5): 577-90, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24434313

RESUMO

Multiple checkpoints regulating finely balanced death-versus-survival decisions characterize both thymic development and peripheral homeostasis of T lymphocytes. While exploring the mechanisms of T cell death involved at various stages during the life of a T cell, we have observed and reported a variety of non-redundant roles for apoptosis inducing factor (Aif), a mitochondrial flavoprotein. Aif is ubiquitously expressed in all cell lineages and functions as an NADH oxidase in its mitochondrial location. It is released following the mitochondrial death signals, whereupon it translocates to the nucleus, binds to DNA and causes large-scale DNA fragmentation. During T cell development, Aif is important for developing thymocytes to navigate the double negative (DN)3 to DN4 transition (beta-selection), via its oxidoreductase property which protects the rapidly proliferating cells from death due to reactive oxygen species (ROS). In peripheral mature T cells, Aif deficiency leads to an increased susceptibility of T cell blasts to activation induced cell death (AICD), possibly mediated by its antioxidant function, and decreased sensitivity to neglect-induced death (NID). Thus, Aif seems to have pro-apoptotic and anti-apoptotic roles in the same lineage in different contexts and at different stages. Surprisingly, in the closely related B lymphocyte lineage, Aif deficiency does not result in any abnormality. These findings generate the possibility of specific T cell dysfunction in human disease caused by Aif deficiency, as well as in mitochondriopathies due to other causes. Also, these data raise questions regarding the basis of lineage-specific consequences of the dysfunction/deficiency of apparently ubiquitous molecules.


Assuntos
Fator de Indução de Apoptose/metabolismo , Diferenciação Celular/genética , Linfócitos T/metabolismo , Timo/crescimento & desenvolvimento , Antioxidantes/metabolismo , Apoptose/genética , Fator de Indução de Apoptose/genética , Linhagem da Célula/imunologia , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Complexos Multienzimáticos/metabolismo , NADH NADPH Oxirredutases/metabolismo , Linfócitos T/imunologia , Timo/metabolismo
4.
J Clin Invest ; 132(9)2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35316223

RESUMO

T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) negatively regulates innate and adaptive immunity in cancer. To identify the mechanisms of Tim-3 in cancer immunity, we evaluated the effects of Tim-3 blockade in human and mouse melanoma. Here, we show that human programmed cell death 1-positive (PD-1+) Tim-3+CD8+ tumor-infiltrating lymphocytes (TILs) upregulate phosphatidylserine (PS), a receptor for Tim-3, and acquire cell surface myeloid markers from antigen-presenting cells (APCs) through transfer of membrane fragments called trogocytosis. Tim-3 blockade acted on Tim-3+ APCs in a PS-dependent fashion to disrupt the trogocytosis of activated tumor antigen-specific CD8+ T cells and PD-1+Tim-3+ CD8+ TILs isolated from patients with melanoma. Tim-3 and PD-1 blockades cooperated to disrupt trogocytosis of CD8+ TILs in 2 melanoma mouse models, decreasing tumor burden and prolonging survival. Deleting Tim-3 in dendritic cells but not in CD8+ T cells impeded the trogocytosis of CD8+ TILs in vivo. Trogocytosed CD8+ T cells presented tumor peptide-major histocompatibility complexes and became the target of fratricide T cell killing, which was reversed by Tim-3 blockade. Our findings have uncovered a mechanism Tim-3 uses to limit antitumor immunity.


Assuntos
Receptor Celular 2 do Vírus da Hepatite A/imunologia , Melanoma , Animais , Linfócitos T CD8-Positivos , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Linfócitos do Interstício Tumoral , Melanoma/patologia , Camundongos , Receptor de Morte Celular Programada 1 , Trogocitose
5.
Ann Otol Rhinol Laryngol ; 130(9): 1069-1077, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33576238

RESUMO

OBJECTIVES: Previous work showed that higher polyp mast cell load correlated with worse postoperative endoscopic appearance in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Polyp epithelial mast cells showed increased expression of T-cell/transmembrane immunoglobulin and mucin domain protein 3 (TIM-3), a receptor that promotes mast cell activation and cytokine production. In this study, CRSwNP patients were followed post-operatively to investigate whether mast cell burden or TIM-3 expression among mast cells can predict recalcitrant disease. METHODS: Nasal polyp specimens were obtained via functional endoscopic sinus surgery (FESS) and separated into epithelial and stromal layers via enzymatic digestion. Mast cells and TIM-3-expressing mast cells were identified via flow cytometry. Mann-Whitney U tests and Cox proportional hazard models assessed whether mast cell burden and TIM-3 expression were associated with clinical outcomes, including earlier recurrence of polypoid edema and need for treatment with steroids. RESULTS: Twenty-three patients with CRSwNP were studied and followed for 6 months after undergoing FESS. Higher mast cell levels were associated with earlier recurrence of polypoid edema: epithelial HR = 1.283 (P = .02), stromal HR = 1.103 (P = .02). Percent of mast cells expressing TIM-3 in epithelial or stromal layers was not significantly associated with earlier recurrence of polypoid edema. Mast cell burden and TIM-3+ expression were not significantly associated with need for future treatment with steroids post-FESS. CONCLUSIONS: Mast cell load in polyp epithelium and stroma may predict a more refractory postoperative course for CRSwNP patients. The role of TIM-3 in the chronic inflammatory state seen in CRSwNP remains unclear.


Assuntos
Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Mastócitos/patologia , Pólipos Nasais/patologia , Rinite/patologia , Sinusite/patologia , Adulto , Contagem de Células , Doença Crônica , Endoscopia , Feminino , Citometria de Fluxo , Humanos , Masculino , Mastócitos/metabolismo , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Pólipos Nasais/metabolismo , Pólipos Nasais/cirurgia , Procedimentos Cirúrgicos Nasais , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Rinite/metabolismo , Rinite/cirurgia , Teste de Desfecho Sinonasal , Sinusite/metabolismo , Sinusite/cirurgia
6.
Sci Signal ; 14(687)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131021

RESUMO

Expression of the transmembrane protein Tim-3 is increased on dysregulated T cells undergoing chronic activation, including during chronic infection and in solid tumors. Thus, Tim-3 is generally thought of as an inhibitory protein. We and others previously reported that under some circumstances, Tim-3 exerts paradoxical costimulatory activity in T cells (and other cells), including enhancement of the phosphorylation of ribosomal S6 protein. Here, we examined the upstream signaling pathways that control Tim-3-mediated increases in phosphorylated S6 in T cells. We also defined the localization of Tim-3 relative to the T cell immune synapse and its effects on downstream signaling. Recruitment of Tim-3 to the immune synapse was mediated exclusively by the transmembrane domain, replacement of which impaired the ability of Tim-3 to costimulate T cell receptor (TCR)-dependent S6 phosphorylation. Furthermore, enforced localization of the Tim-3 cytoplasmic domain to the immune synapse in a chimeric antigen receptor still enabled T cell activation. Together, our findings are consistent with a model whereby Tim-3 enhances TCR-proximal signaling under acute conditions.


Assuntos
Receptor Celular 2 do Vírus da Hepatite A , Sinapses Imunológicas , Proteínas Proto-Oncogênicas c-akt , Receptor Celular 2 do Vírus da Hepatite A/genética , Humanos , Ativação Linfocitária , Sistema de Sinalização das MAP Quinases , Infecção Persistente , Proteínas Proto-Oncogênicas c-akt/genética
7.
Cell Rep ; 36(11): 109699, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34525351

RESUMO

Regulatory T cells (Treg cells) are critical mediators of self-tolerance, but they can also limit effective anti-tumor immunity. Although under homeostasis a small fraction of Treg cells in lymphoid organs express the putative checkpoint molecule Tim-3, this protein is expressed by a much larger proportion of tumor-infiltrating Treg cells. Using a mouse model that drives cell-type-specific inducible Tim-3 expression, we show that expression of Tim-3 by Treg cells is sufficient to drive Treg cells to a more effector-like phenotype, resulting in increases in suppressive activity, effector T cell exhaustion, and tumor growth. We also show that T-reg-cell-specific inducible deletion of Tim-3 enhances anti-tumor immunity. Enhancement of Treg cell function by Tim-3 is strongly correlated with increased expression of interleukin-10 (IL-10) and a shift to a more glycolytic metabolic phenotype. Our data demonstrate that Tim-3+ Treg cells may be a relevant therapeutic target cell type for the treatment of cancer.


Assuntos
Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Linfócitos T Reguladores/metabolismo , Microambiente Tumoral , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Regulação da Expressão Gênica , Glicólise , Receptor Celular 2 do Vírus da Hepatite A/deficiência , Receptor Celular 2 do Vírus da Hepatite A/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Masculino , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação Oxidativa , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Serina-Treonina Quinases TOR/metabolismo
8.
F1000Res ; 7: 316, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29560265

RESUMO

T-cell immunoglobulin and mucin domain 3 (Tim-3) is a transmembrane protein that in both mice and humans has been shown to possess various functions in a context-dependent manner. Thus, Tim-3 has been associated with both inhibitory and co-stimulatory function, depending in part on the specific cell type and immune response course. Though originally described on T cells, Tim-3 is now known to be expressed by both lymphoid and non-lymphoid cells within the immune system and even by non-immune cells. In addition, though widely thought of as a negative regulator of immunity, Tim-3 has been shown in more recent studies to have a positive function on both myeloid and lymphoid cells, including T cells. Tim-3 is often expressed at a high level on exhausted T cells in tumors and chronic infection and may engage in crosstalk with other so-called "checkpoint" molecules such as PD-1. Thus, Tim-3 has emerged as a possible therapeutic target, which is being actively explored both pre-clinically and clinically. However, recent research suggests a more complex in vivo role for this protein, compared with other targets in this area.

9.
J Exp Med ; 209(9): 1641-53, 2012 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-22869892

RESUMO

Apoptosis-inducing factor (Aif) is a mitochondrial flavoprotein that regulates cell metabolism and survival in many tissues. We report that aif-hypomorphic harlequin (Hq) mice show thymic hypocellularity and a cell-autonomous thymocyte developmental block associated with apoptosis at the ß-selection stage, independent of T cell receptor ß recombination. No abnormalities are observed in the B cell lineage. Transgenes encoding wild-type or DNA-binding-deficient mutant Aif rectify the thymic defect, but a transgene encoding oxidoreductase activity-deficient mutant Aif does not. The Hq thymic block is reversed in vivo by antioxidant treatment, and Hq T but not B lineage cells show enhanced oxidative stress. Thus, Aif, a ubiquitous protein, serves a lineage-specific nonredundant antiapoptotic role in the T cell lineage by regulating reactive oxygen species during thymic ß-selection.


Assuntos
Fator de Indução de Apoptose/fisiologia , Linfócitos T/fisiologia , Animais , Apoptose , Morte Celular , Linhagem da Célula , DNA/metabolismo , Feminino , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Masculino , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Espécies Reativas de Oxigênio/metabolismo , Recombinação Genética , Timócitos/metabolismo , Timócitos/patologia , Timo/crescimento & desenvolvimento , Timo/patologia
10.
J Immunol ; 179(2): 797-803, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17617569

RESUMO

Apoptosis-inducing factor (Aif) is a mitochondrial flavoprotein with multiple roles in apoptosis as well as in cellular respiration and redox regulation. The harlequin (Hq) mouse strain carries an aif locus modification causing reduced Aif expression. We demonstrate that activated CD4(+) and CD8(+) peripheral T cells from Hq mice show resistance to neglect-induced death (NID) triggered by growth factor withdrawal, but not to death induced by multiple agents that trigger DNA damage. Aif translocates to the nucleus in cells undergoing NID, and, in Hq T cell blasts, resistance to NID is associated with reduced cytosolic release of mitochondrial cytochrome c, implicating Aif in this event. In contrast, Hq T cell blasts express higher levels of CD95L, demonstrating increased susceptibility to activation-induced cell death (AICD) and apoptosis triggered by hydrogen peroxide. Superoxide scavenging protects from AICD in wild-type, but not Hq, T cell blasts, suggesting that Aif plays a crucial superoxide-scavenging role to regulate T cell AICD. Finally, the altered pattern of death susceptibility is reproduced by siRNA-mediated reduction of Aif expression in normal T cells. Thus, Aif serves nonredundant roles, both proapoptotic and antiapoptotic, in activated peripheral T cells.


Assuntos
Fator de Indução de Apoptose/metabolismo , Apoptose/fisiologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Animais , Fator de Indução de Apoptose/imunologia , Western Blotting , Diferenciação Celular/imunologia , Citometria de Fluxo , Camundongos , Camundongos Mutantes , Microscopia Confocal , Mitocôndrias/metabolismo , Mitocôndrias/patologia , RNA Interferente Pequeno , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/citologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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