RESUMO
γδ T cells are important immunoregulatory cells in experimental autoimmune uveitis (EAU), and the activation status of γδ T cells determines their disease-enhancing or inhibitory effects. Because γδ T cells can be activated via various pathways, we questioned whether the nature of their activation might impact their function. In this study, we show that γδ T cells activated under different inflammatory conditions differ greatly in their functions. Whereas anti-CD3 treatment activated both IFN-γ+ and IL-17+ γδ T cells, cytokines preferentially activated IL-17+ γδ T cells. γδ T cells continued to express high levels of surface CD73 after exposure to inflammatory cytokines, but they downregulated surface CD73 after exposure to dendritic cells. Although both CD73high and CD73low cells have a disease-enhancing effect, the CD73low γδ T cells are less inhibitory. We also show that polarized activation not only applies to αß T cells and myeloid cells, but also to γδ T cells. After activation under Th17-polarizing conditions, γδ T cells predominantly expressed IL-17 (gdT17), but after activation under Th1 polarizing conditions (gdT1) they mainly expressed IFN-γ. The pro-Th17 activity of γδ T cells was associated with gdT17, but not gdT1. Our results demonstrate that the functional activity of γδ T cells is strikingly modulated by their activation level, as well as the pathway through which they were activated.
Assuntos
Interferon gama/imunologia , Interleucina-17/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Células Th17/imunologia , Uveíte/imunologia , 5'-Nucleotidase/metabolismo , Animais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Citocinas/imunologia , Células Dendríticas/imunologia , Feminino , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subpopulações de Linfócitos T/imunologia , Células Th1/imunologia , Uveíte/induzido quimicamente , Uveíte/patologiaRESUMO
The γδ T cells play an important role in both mice and humans as a source of the cytokine IL-17, which is key for immune resistance to certain pathogens. In mice, most of these IL-17 producers, termed γδT-17 cells, actually comprise two distinct types: those expressing an invariant Vγ6Vδ1+ TCR and those expressing a Vγ4+ TCR. Murine γδT-17 cells acquire an inherent bias to produce IL-17 and other "type 17" cytokines during thymic development. The similarities and differences between the two mouse γδT-17 types are reviewed here, and the potential implications of their differences are discussed. There is some evidence that two distinct TCR-defined IL-17-producing γδ T cell subsets also exist in humans, but unlike the mouse γδT-17 cells, these cells are probably not imprinted with an IL-17 bias during thymic development, but rather acquire an IL-17 bias in the periphery.
Assuntos
Interleucina-17 , Receptores de Antígenos de Linfócitos T gama-delta , Animais , Citocinas , Camundongos , Subpopulações de Linfócitos TRESUMO
Th17-type autoreactive T cells contribute to pathogenicity in autoimmune diseases, including autoimmune uveitis. However, the mechanisms of regulation of Th17 cell activities remain unsolved and are likely to be tissue- and disease specific. In this review, we have summarized our studies from the murine model of experimental autoimmune uveitis (EAU). The resultsdemonstrate that γδ T cells have a regulatory effect on Th17 response. The regulatory effects of γδ T cells depend on their action state. Activated γδ T cells express significantly high levels of adenosine receptor A2 (A2AR) but low CD73. Both molecules are crucially involved in adenosine generation, thus modifying T cell responses. While the increased expression of A2AR-allows activated γδ T cells to bind adenosine more effectively than other immune cells, the decreased CD73 restricts their ability to convert AMP to adenosine. Adenosine affects Th1 and Th17 autoimmune responses differently. Its activation of γδ T cells shifts the Th1/Th17 balance towards the Th17 autoreactivity.
Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Células Th17/imunologia , Uveíte/imunologia , Animais , Humanos , Linfócitos T Reguladores/imunologia , Células Th1/imunologiaRESUMO
Regulatory effects of γδ T-cells on immune responses have been studied for years. We have investigated the regulatory effect of γδ T-cells on Th1 and Th17 autoimmune responses, and have studied molecular and cellular mechanisms by which γδ T-cells enhance or inhibit immune responses, exploiting a well-characterized murine model of experimental autoimmune uveitis (EAU). Our results show that (1) aberrant γδ T-cell activation is an important pathogenic event in EAU; (2) γδ T-cells have a unique regulatory effect on Th17 autoimmune responses, which is shaped by the activation status of γδ T-cells; and (3) γδ-mediated immunoregulation is closely linked with the extracellular adenosine metabolism. Reciprocal interactions between γδ T-cells and extracellular adenosine partially determine the development of EAU.
Assuntos
Doenças Autoimunes/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Uveíte/imunologia , Adenosina , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Modelos Animais , Receptores de Antígenos de Linfócitos T gama-delta/genéticaRESUMO
We previously reported that selective ablation of certain γδ T cell subsets, rather than removal of all γδ T cells, strongly affects serum Ab levels in nonimmunized mice. This type of manipulation also changed T cells, including residual γδ T cells, revealing some interdependence of γδ T cell populations. For example, in mice lacking Vγ4(+) and Vγ6(+) γδ T cells (B6.TCR-Vγ4(-/-)/6(-/-)), we observed expanded Vγ1(+) cells, which changed in composition and activation and produced more IL-4 upon stimulation in vitro, increased IL-4 production by αß T cells as well as spontaneous germinal center formation in the spleen, and elevated serum Ig and autoantibodies. We therefore examined B cell populations in this and other γδ-deficient mouse strains. Whereas immature bone marrow B cells remained largely unchanged, peripheral B cells underwent several changes. Specifically, transitional and mature B cells in the spleen of B6.TCR-Vγ4(-/-)/6(-/-) mice and other peripheral B cell populations were diminished, most of all splenic marginal zone (MZ) B cells. However, relative frequencies and absolute numbers of Ab-producing cells, as well as serum levels of Abs, IL-4, and BAFF, were increased. Cell transfers confirmed that these changes are directly dependent on the altered γδ T cells in this strain and on their enhanced potential of producing IL-4. Further evidence suggests the possibility of direct interactions between γδ T cells and B cells in the splenic MZ. Taken together, these data demonstrate the capability of γδ T cells of modulating size and productivity of preimmune peripheral B cell populations.
Assuntos
Linfócitos B/imunologia , Interleucina-4/biossíntese , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Baço/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Anticorpos/sangue , Autoanticorpos/sangue , Fator Ativador de Células B/sangue , Células Cultivadas , Técnicas de Cocultura , Centro Germinativo/imunologia , Imunoglobulina G/sangue , Interleucina-4/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T gama-delta/genética , Baço/citologia , Subpopulações de Linfócitos T/transplanteRESUMO
γδ T cells can influence specific antibody responses. Here, we report that mice deficient in individual γδ T-cell subsets have altered levels of serum antibodies, including all major subclasses, sometimes regardless of the presence of αß T cells. One strain with a partial γδ deficiency that increases IgE antibodies also displayed increases in IL-4-producing T cells (both residual γδ T cells and αß T cells) and in systemic IL-4 levels. Its B cells expressed IL-4-regulated inhibitory receptors (CD5, CD22, and CD32) at diminished levels, whereas IL-4-inducible IL-4 receptor α and MHCII were increased. They also showed signs of activation and spontaneously formed germinal centers. These mice displayed IgE-dependent features found in hyper-IgE syndrome and developed antichromatin, antinuclear, and anticytoplasmic autoantibodies. In contrast, mice deficient in all γδ T cells had nearly unchanged Ig levels and did not develop autoantibodies. Removing IL-4 abrogated the increases in IgE, antichromatin antibodies, and autoantibodies in the partially γδ-deficient mice. Our data suggest that γδ T cells, controlled by their own cross-talk, affect IL-4 production, B-cell activation, and B-cell tolerance.
Assuntos
Linfócitos B/imunologia , Tolerância Imunológica , Interleucina-4/biossíntese , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Transferência Adotiva , Animais , Anticorpos/sangue , Autoanticorpos/sangue , Linfócitos B/citologia , Feminino , Centro Germinativo/metabolismo , Imunização , Imunoglobulina E/sangue , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Fenótipo , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Baço/citologiaRESUMO
To prevent potentially damaging inflammatory responses, the eye actively promotes local immune tolerance via a variety of mechanisms. Owing to trauma, infection, or other ongoing autoimmunity, these mechanisms sometimes fail, and an autoimmune disorder may develop in the eye. In mice of the C57BL/10 (B10) background, autoimmune keratitis often develops spontaneously, particularly in the females. Its incidence is greatly elevated in the absence of γδ T cells, such that â¼80% of female B10.TCRδ(-/-) mice develop keratitis by 18 wk of age. In this article, we show that CD8(+) αß T cells are the drivers of this disease, because adoptive transfer of CD8(+), but not CD4(+), T cells to keratitis-resistant B10.TCRß/δ(-/-) hosts induced a high incidence of keratitis. This finding was unexpected because in other autoimmune diseases, more often CD4(+) αß T cells, or both CD4(+) and CD8(+) αß T cells, mediate the disease. Compared with wild-type B10 mice, B10.TCRδ(-/-) mice also show increased percentages of peripheral memory phenotype CD8(+) αß T cells, along with an elevated frequency of CD8(+) αß T cells biased to produce inflammatory cytokines. In addition, B10.TCRδ-/- mice have fewer peripheral CD4(+) CD25(+) Foxp3(+) αß regulatory T cells (Tregs), which express lower levels of receptors needed for Treg development and function. Together, these observations suggest that in B10 background mice, γδ T cells are required to generate adequate numbers of CD4(+) CD25(+) Foxp3(+) Tregs, and that in B10.TCRδ(-/-) mice a Treg deficiency allows dysregulated effector or memory CD8(+) αß T cells to infiltrate the cornea and provoke an autoimmune attack.
Assuntos
Doenças Autoimunes/imunologia , Córnea/imunologia , Ceratite/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Progressão da Doença , Feminino , Fatores de Transcrição Forkhead , Memória Imunológica , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/genéticaRESUMO
Changes made in the 8th edition of the Guide for the Care and Use of Laboratory Animals included new recommendations for the amount of space for breeding female mice. Adopting the new recommendations required, in essence, the elimination of trio breeding practices for all institutions. Both public opinion and published data did not readily support the new recommendations. In response, the National Jewish Health Institutional Animal Care and Use Committee established a program to directly compare the effects of breeding format on mouse pup survival and growth. Our study showed an overall parity between trio and pairwise breeding formats on the survival and growth of the litters, suggesting that the housing recommendations for breeding female mice as stated in the current Guide for the Care and Use of Laboratory Animals should be reconsidered.
Assuntos
Cruzamento/métodos , Abrigo para Animais/ética , Animais , Autoimunidade , Peso Corporal , Cruzamento/legislação & jurisprudência , Feminino , Guias como Assunto , Abrigo para Animais/legislação & jurisprudência , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , GravidezRESUMO
Over the last several years, a number of papers have called attention to a distinct population of γδ T cells preferentially found in the dermis of the skin of normal mice. These cells appear to play an important role in promoting the development of psoriasis, but also are critical for host resistance to particular pathogens. They are characterized by the expression of a limited subset of γδ T cell receptors and a strong propensity to secrete IL-17. Perhaps most importantly, humans appear to carry an equivalent dermal γδ T cell population, likewise biased to secrete IL-17 and also implicated as playing a pathogenic role in psoriasis. This review will attempt to summarize and reconcile recent findings concerning the dermal γδ T cells.
Assuntos
Derme/imunologia , Interleucina-17/imunologia , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Animais , Humanos , Inflamação/imunologia , Interleucina-17/metabolismo , Camundongos , Psoríase/imunologiaRESUMO
Immunoglobulin E (IgE) antibodies play a crucial role in host defense against parasite infections. However, inappropriate IgE responses are also involved in the pathogenesis of allergic diseases. The generation of IgE antibodies is a tightly controlled process regulated by multiple transcription factors, cytokines, and immune cells including γδ T cells. Accumulating evidence demonstrates that γδ T cells play a critical role in regulating IgE responses; however, both IgE-enhancing and IgE-suppressive effects are suggested for these cells in different experimental systems. In this review, we examine the available evidence and discuss the role of γδ T cells in IgE regulation both in the context of antigen-induced immune responses and in the state of partial immunodeficiency.
Assuntos
Imunoglobulina E/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Animais , Antígenos/imunologia , Humanos , Switching de ImunoglobulinaRESUMO
We have previously reported that, depending on their activation status, mouse γδ T cells can either enhance or inhibit the activity of IL-17(+) autoreactive T cells in experimental autoimmune uveitis. In this study, we showed that γδ T cells in naive C57BL/6 (B6) mouse do not express the IL-23R, whereas in immunized mice, it is expressed on >50% of γδ T cells. In vitro studies showed that IL-23R expression on γδ T cells is modulated by their state of activation, as weakly activated γδ T cells expressed the IL-23R, but highly activated γδ T cells did not. Functional studies showed that IL-23R(+) γδ T cells had the strongest suppressive effect on IL-17(+) autoreactive T cells, and that this effect was inhibited when the IL-23R was blocked by anti-IL-23R Ab or in the presence of excessive amounts of exogenous IL-23. We conclude that the balance between the enhancing and inhibitory effects of γδ T cells is regulated by their level of IL-23R expression. The expression of variable IL-23R levels allows γδ T cells to have different regulatory effects on adaptive immune responses, conceivably as a result of αß and γδ T cells competing for IL-23.
Assuntos
Doenças Autoimunes/imunologia , Interleucina-17/metabolismo , Interleucina-23/farmacologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Interleucina/imunologia , Linfócitos T/imunologia , Uveíte/imunologia , Animais , Anticorpos/imunologia , Autoimunidade , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Interleucina/biossíntese , Linfócitos T/metabolismo , Uveíte/induzido quimicamenteRESUMO
We re-examined the observation that γδ T cells, when transferred from mice tolerized to an inhaled conventional Ag, suppress the allergic IgE response to this Ag specifically. Using OVA and hen egg lysozyme in crisscross fashion, we confirmed the Ag-specific IgE-regulatory effect of the γδ T cells. Although only Vγ4(+) γδ T cells are regulators, the Ag specificity does not stem from specificity of their γδ TCRs. Instead, the Vγ4(+) γδ T cells failed to respond to either Ag, but rapidly acquired Ag-specific regulatory function in vivo following i.v. injection of non-T cells derived from the spleen of Ag-tolerized mice. This correlated with their in vivo Ag acquisition from i.v. injected Ag-loaded splenic non-T cells, and in vivo transfer of membrane label provided evidence for direct contact between the injected splenic non-T cells and the Vγ4(+) γδ T cells. Together, our data suggest that Ag itself, when acquired by γδ T cells, directs the specificity of their IgE suppression.
Assuntos
Antígenos/imunologia , Asma/imunologia , Imunoglobulina E/imunologia , Muramidase/imunologia , Ovalbumina/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/análise , Subpopulações de Linfócitos T/imunologia , Administração por Inalação , Transferência Adotiva , Aerossóis , Animais , Antígenos/administração & dosagem , Antígenos/toxicidade , Asma/etiologia , Separação Celular , Feminino , Humanos , Tolerância Imunológica , Sinapses Imunológicas , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Muramidase/administração & dosagem , Muramidase/toxicidade , Ovalbumina/administração & dosagem , Ovalbumina/toxicidade , Baço/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/transplanteRESUMO
In the current study, we showed that in vivo administration of an anti-CD25 Ab (PC61) decreased the Th17 response in C57BL/6 mice immunized with the uveitogenic peptide interphotoreceptor retinoid-binding protein, while enhancing the autoreactive Th1 response. The depressed Th17 response was closely associated with decreased numbers of a splenic dendritic cell (DC) subset expressing CD11c(+)CD3(-)CD25(+) and decreased expansion of γδ T cells. We demonstrated that ablation of the CD25(+) DC subset accounted for the decreased activation and the expansion of γδ T cells, leading to decreased activation of IL-17(+) interphotoreceptor retinoid-binding protein-specific T cells. Our results show that an enhanced Th17 response in an autoimmune disease is associated with the appearance of a DC subset expressing CD25 and that treatment of mice with anti-CD25 Ab causes functional alterations in a number of immune cell types, namely DCs and γδ T cells, in addition to CD25(+)αßTCR(+) regulatory T cells.
Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Células Th17/imunologia , Uveíte/imunologia , Uveíte/patologia , Animais , Doenças Autoimunes/metabolismo , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Feminino , Subunidade alfa de Receptor de Interleucina-2/fisiologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células Th17/patologia , Uveíte/metabolismoRESUMO
The gammadelta T lmphocytes are often divided into subsets based upon expression of certain TCR components. This division was initially made because gammadelta T cells residing in particular epithelia were found to show tissue specific differences in their TCRs. Many examples now show that gammadelta T cell subsets also appear to be biased to carry out particular functions. This suggests that particular gammadelta TCR types direct the cells to acquire a certain type of functional programming during thymic development. Here, we describe functionally distinct, TCR-defined gammadelta T cell subsets, and evidence that their functions are predetermined in the thymus.
Assuntos
Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Diferenciação Celular , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Subpopulações de Linfócitos T/citologia , Timo/citologia , Timo/imunologiaRESUMO
It has been demonstrated that the two main subsets of peripheral γδ T cells, Vγ1 and Vγ4, have divergent functions in many diseases models. Recently, we reported that Vγ4 γδ T cells played a protective role in tumor immunity through eomesodermin-controlled mechanisms. However, the precise roles of Vγ1 γδ T cells in tumor immunity, especially whether Vγ1 γδ T cells have any interaction with Vγ4 γδ T cells, remain unknown. We demonstrated in this paper that Vγ1 γδ T cells suppressed Vγ4 γδ T cell-mediated antitumor function both in vitro and in vivo, and this suppression was cell contact independent. Using neutralizing anti-IL-4 Ab or IL-4(-/-) mice, we determined the suppressive factor derived from Vγ1 γδ T cells was IL-4. Indeed, treatment of Vγ4 γδ T cells with rIL-4 significantly reduced expression levels of NKG2D, perforin, and IFN-γ. Finally, Vγ1 γδ T cells produced more IL-4 and expressed significantly higher level of GATA-3 upon Th2 priming in comparison with Vγ4 γδ T cells. Therefore, to our knowledge, our results established for the first time a negative regulatory role of Vγ1 γδ T cells in Vγ4 γδ T cell-mediated antitumor immunity through cell contact-independent and IL-4-mediated mechanisms. Selective depletion of this suppressive subset of γδ T cells may be beneficial for tumor immune therapy.
Assuntos
Regulação para Baixo/imunologia , Interleucina-4/biossíntese , Receptores de Antígenos de Linfócitos T gama-delta/biossíntese , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia , Animais , Comunicação Celular/genética , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Regulação para Baixo/genética , Interleucina-4/deficiência , Interleucina-4/genética , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/prevenção & controle , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T gama-delta/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T gama-delta/genética , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Microambiente Tumoral/genéticaRESUMO
Although the TNF receptor family member CD27 has been known for some time, its functional role as a coreceptor on T and B cells remains poorly understood. Recent reports have shown that CD27 and its ligand CD70 play a critical role in the development and function of γδ T cells in mice. In this issue of the European Journal of Immunology, a study now extends these findings to the Vγ9Vδ2(+) subset of human γδ T cells. This subset, whose responses are readily elicited by phosphoantigens, plays an important role in anti-tumor immune responses. This study shows that most Vγ9Vδ2(+) cells express CD27, and signaling via the CD27-CD70 axis is needed for their survival, proliferation and cytokine secretion. Moreover, CD27 functions as a coreceptor, which promotes, in conjunction with TCR-mediated signals, expansion of Th1-biased Vγ9Vδ2(+) cells. This new information underscores the significance of CD27 in γδ T-cell functional differentiation, and is likely to facilitate the development of γδ T-cell-based clinical immunotherapy.