RESUMEN
Tissue-resident memory T cells (TRM) provide optimal defense at the sites of infection, but signals regulating their development are unclear, especially for CD4 T cells. Here we identify two distinct pathways that lead to the generation of CD4 TRM in the lungs following influenza infection. The TRM are transcriptionally distinct from conventional memory CD4 T cells and share a gene signature with CD8 TRM. The CD4 TRM are superior cytokine producers compared with conventional memory cells, can protect otherwise naive mice against a lethal influenza challenge, and display functional specialization by inducing enhanced inflammatory responses from dendritic cells compared with conventional memory cells. Finally, we demonstrate than an interleukin (IL)-2-dependent and a novel IL-2-independent but IL-15-dependent pathway support the generation of cohorts of lung TRM.
Asunto(s)
Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/fisiología , Células Dendríticas/inmunología , Interleucina-15/metabolismo , Pulmón/inmunología , Infecciones por Orthomyxoviridae/inmunología , Orthomyxoviridae/inmunología , Animales , Diferenciación Celular , Células Cultivadas , Memoria Inmunológica , Mediadores de Inflamación/metabolismo , Interleucina-15/genética , Interleucina-2/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , TranscriptomaRESUMEN
The mechanisms responsible for heterosubtypic immunity to influenza virus are not well understood but might hold the key for new vaccine strategies capable of providing lasting protection against both seasonal and pandemic strains. Memory CD4 T cells are capable of providing substantial protection against influenza both through direct effector mechanisms and indirectly through regulatory and helper functions. Here, we discuss the broad impact of memory CD4 T cells on heterosubtypic immunity against influenza and the prospects of translating findings from animal models into improved human influenza vaccines.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Memoria Inmunológica/inmunología , Vacunas contra la Influenza/inmunología , Gripe Humana/inmunología , Humanos , Inmunidad Celular/fisiología , Gripe Humana/prevención & controlRESUMEN
Protection against tuberculosis depends upon the generation of CD4(+) T cell effectors capable of producing IFN-gamma and stimulating macrophage antimycobacterial function. Effector CD4(+) T cells are known to express CD44(hi)CD62L(lo) surface phenotype. In this paper we demonstrate that a population of CD44(hi)CD62L(lo) CD4(+) effectors generated in response to Mycobacterium bovis BCG or M. tuberculosis infection in C57BL/6 mice is heterogeneous and consists of CD27(hi) and CD27(lo) T cell subsets. These subsets exhibit a similar degree of in vivo proliferation, but differ by the capacity for IFN-gamma production. Ex vivo isolated CD27(lo) T cells express higher amounts of IFN-gamma RNA and contain higher frequencies of IFN-gamma producers compared to CD27(hi) subset, as shown by real-time PCR, intracellular staining for IFN-gamma and ELISPOT assays. In addition, CD27(lo) CD4(+) T cells uniformly express CD44(hi)CD62L(lo) phenotype. We propose that CD27(lo) CD44(hi)CD62L(lo) CD4(+) T cells represent highly differentiated effector cells with a high capacity for IFN-gamma secretion and antimycobacterial protection at the site of infection.
Asunto(s)
Vacuna BCG/inmunología , Interferón gamma/inmunología , Pulmón/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Tuberculosis/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Animales , División Celular/inmunología , Células Cultivadas , Femenino , Receptores de Hialuranos/inmunología , Selectina L/inmunología , Ratones , Ratones Endogámicos C57BL , Mycobacterium bovis/inmunología , Fenotipo , ARN Mensajero , Subgrupos de Linfocitos T/inmunologíaRESUMEN
Whether memory T lymphocytes are derived directly from effector T cells or via a separately controlled pathway has long been debated. Here we present evidence that, after adoptive transfer, a large fraction of in vitro--derived effector CD4(+) T cells have the potential to become memory T cells and that this transition can occur without further division. This data supports a linear pathway from effector to memory cells and suggests that most properties of memory cells are predetermined during effector generation. We suggest, therefore, that evaluation of vaccine efficacy in the induction of memory CD4(+) T cells should focus on the effector stage.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Memoria Inmunológica , Animales , Antígenos CD4/inmunología , Diferenciación Celular/inmunología , División Celular/inmunología , Ratones , Ratones TransgénicosRESUMEN
The immunodeficiency syndrome murine AIDS (MAIDS), caused by the BM5 retrovirus preparation, involves the activation, division, and subsequent anergy of the entire CD4(+) T cell population as well as extensive B cell hyperproliferation and hypergammaglobulinemia, resulting in splenomegaly and lymphadenopathy, followed many weeks later by death. The development of MAIDS requires CD4(+) T cells and MHC class II expression by the infected host, supporting a role for T-B interaction in disease development or progression. To explore this possibility, we examined development of MAIDS in mice deficient in CD4 (CD4 knockout), in which T-B interactions are compromised. We find that in CD4 knockout hosts, BM5 causes T cell immunodeficiency in the remaining T cells but has only a limited ability to induce B cell phenotypic changes, hyperproliferation, hypergammaglobulinemia, or splenomegaly. There is also delayed death of infected mice. This implies that CD4 dependent T-B interaction is needed to induce the B cell aspects of disease and supports a multistep mechanism of disease in which B cell changes follow and are caused by CD4(+) T cell effects.
Asunto(s)
Linfocitos B/inmunología , Linfocitos B/patología , Antígenos CD4/genética , Virus de la Leucemia Murina/inmunología , Leucemia Experimental/genética , Síndrome de Inmunodeficiencia Adquirida del Murino/genética , Infecciones por Retroviridae/genética , Animales , Células Cultivadas , Anergia Clonal/genética , Progresión de la Enfermedad , Hipergammaglobulinemia/genética , Hipergammaglobulinemia/inmunología , Inmunofenotipificación , Leucemia Experimental/inmunología , Leucemia Experimental/mortalidad , Leucemia Experimental/virología , Enfermedades Linfáticas/genética , Enfermedades Linfáticas/inmunología , Activación de Linfocitos/genética , Subgrupos Linfocitarios/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Síndrome de Inmunodeficiencia Adquirida del Murino/inmunología , Síndrome de Inmunodeficiencia Adquirida del Murino/mortalidad , Síndrome de Inmunodeficiencia Adquirida del Murino/virología , Infecciones por Retroviridae/inmunología , Infecciones por Retroviridae/mortalidad , Infecciones por Retroviridae/patología , Esplenomegalia/genética , Esplenomegalia/inmunología , Análisis de Supervivencia , Subgrupos de Linfocitos T/inmunologíaRESUMEN
We have previously shown that systemic staphylococcal enterotoxin A (SEA) injections cause CD4 T cells in TCR-transgenic mice to become tolerant to subsequent ex vivo restimulation. An active IFN-gamma-dependent mechanism of suppression was responsible for the apparent unresponsiveness of the CD4 T cells. In this study, we analyze the response of CD4 T cells isolated throughout the first 10 days of the in vivo response to injected SEA. We show that CD4 T cells isolated at the peak of the in vivo response undergo very little activation-induced cell death after sterile FACS sorting or restimulation in the presence of neutralizing Abs to IFN-gamma. We also show that the IFN-gamma-dependent tolerance develops soon after SEA injection in the spleens of both normal and TCR-transgenic mice. This suppression is dependent upon myeloid cells from the SEA-treated mice and is optimal when inducible NO synthase activity and reactive oxygen intermediates are both present. The data indicate that IFN-gamma, myeloid cells, and a combination of NO and reactive oxygen intermediates all contribute to a common pathway of T cell death that targets activated or responding CD4 T cells. Sorted Gr-1(+) cells from SEA-treated mice also directly suppress the response of naive CD4 T cells in mixed cultures, indicating that this tolerance mechanism may play a role in down-regulating other vigorous immune responses.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Enterotoxinas/inmunología , Tolerancia Inmunológica/inmunología , Interferón gamma/fisiología , Células Mieloides/inmunología , Superantígenos/inmunología , Animales , Antígenos de Diferenciación Mielomonocítica/biosíntesis , Linfocitos T CD4-Positivos/metabolismo , Línea Celular , Separación Celular , Células Cultivadas , Enterotoxinas/administración & dosificación , Inyecciones Intravenosas , Ganglios Linfáticos/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Mieloides/metabolismo , Óxido Nítrico/fisiología , Especies Reactivas de Oxígeno/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/biosíntesis , Bazo/inmunología , Staphylococcus aureus/inmunología , Superantígenos/administración & dosificación , Antígenos Thy-1/biosíntesisRESUMEN
Many receptors for endocytosis recycle into and out of cells through early endosomes. We now find in dendritic cells that the DEC-205 multilectin receptor targets late endosomes or lysosomes rich in major histocompatibility complex class II (MHC II) products, whereas the homologous macrophage mannose receptor (MMR), as expected, is found in more peripheral endosomes. To analyze this finding, the cytosolic tails of DEC-205 and MMR were fused to the external domain of the CD16 Fcgamma receptor and studied in stable L cell transfectants. The two cytosolic domains each mediated rapid uptake of human immunoglobulin (Ig)G followed by recycling of intact CD16 to the cell surface. However, the DEC-205 tail recycled the CD16 through MHC II-positive late endosomal/lysosomal vacuoles and also mediated a 100-fold increase in antigen presentation. The mechanism of late endosomal targeting, which occurred in the absence of human IgG, involved two functional regions: a membrane-proximal region with a coated pit sequence for uptake, and a distal region with an EDE triad for the unusual deeper targeting. Therefore, the DEC-205 cytosolic domain mediates a new pathway of receptor-mediated endocytosis that entails efficient recycling through late endosomes and a greatly enhanced efficiency of antigen presentation to CD4(+) T cells.
Asunto(s)
Presentación de Antígeno/inmunología , Antígenos CD , Células Dendríticas/inmunología , Endocitosis , Antígenos de Histocompatibilidad Clase II/inmunología , Lectinas Tipo C , Lisosomas/metabolismo , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/metabolismo , Receptores de Superficie Celular/inmunología , Receptores de Superficie Celular/metabolismo , Adsorción , Secuencia de Aminoácidos , Animales , Linfocitos T CD4-Positivos/inmunología , Células Cultivadas , Células Dendríticas/citología , Células Dendríticas/metabolismo , Endosomas/metabolismo , Citometría de Flujo , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Células L , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Ratones , Antígenos de Histocompatibilidad Menor , Datos de Secuencia Molecular , Receptores de Superficie Celular/química , Receptores de Superficie Celular/genética , Receptores de IgG/genética , Receptores de IgG/inmunología , Receptores de IgG/metabolismo , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/metabolismo , Alineación de Secuencia , TransfecciónRESUMEN
Efficient peptide presentation by professional APC to naive and effector CD4 T cells in vitro is limited to the first 1-2 days of culture, but is nonetheless optimum for effector expansion and cytokine production. In fact, prolonging Ag presentation leads to high levels of T cell death, decreased effector expansion, and decreased cytokine production by recovered effectors. Despite the absence of Ag presentation beyond day 2, T cell division continues at a constant rate throughout the 4-day culture. The Ag-independent later stage depends on the presence of IL-2, and we conclude optimum effector generation depends on an initial 2 days of TCR stimulation followed by an additional 2 days of Ag-independent, cytokine driven T cell expansion and differentiation.
Asunto(s)
Antígenos/fisiología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Ciclo Celular/inmunología , Citocinas/fisiología , Memoria Inmunológica , Secuencia de Aminoácidos , Animales , Presentación de Antígeno , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Antígenos T-Independientes/fisiología , Diferenciación Celular/inmunología , División Celular/inmunología , Línea Celular , Células Cultivadas , Columbidae , Grupo Citocromo c/inmunología , Relación Dosis-Respuesta Inmunológica , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Datos de Secuencia Molecular , Factores de TiempoRESUMEN
In Mycobacterium bovis Bacille Calmette-Guérin (BCG)-infected wild-type mice, there was a large expansion of an activated (CD44(hi)) splenic CD4 T cell population followed by a rapid contraction of this population to normal numbers. Contraction of the activated CD4 T cell population in wild-type mice was associated with increased apoptosis of activated CD4 T cells. In BCG-infected interferon (IFN)-gamma knockout (KO) mice, the activated CD4 T cell population did not undergo apoptosis. These mice accumulated large numbers of CD4(+)CD44(hi) T cells that were responsive to mycobacterial antigens. Addition of IFN-gamma to cultured splenocytes from BCG-infected IFN-gamma KO mice induced apoptosis of activated CD4 T cells. IFN-gamma-mediated apoptosis was abolished by depleting adherent cells or Mac-1(+) spleen cells or by inhibiting nitric oxide synthase. Thus, IFN-gamma is essential to a regulatory mechanism that eliminates activated CD4 T cells and maintains CD4 T cell homeostasis during an immune response.
Asunto(s)
Apoptosis , Linfocitos T CD4-Positivos/inmunología , Interferón gamma/inmunología , Mycobacterium bovis , Tuberculosis/inmunología , Animales , Linfocitos T CD4-Positivos/patología , Adhesión Celular , Células Cultivadas , Separación Inmunomagnética , Interferón gamma/deficiencia , Interferón gamma/genética , Activación de Linfocitos , Depleción Linfocítica , Antígeno de Macrófago-1/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa/antagonistas & inhibidores , Bazo/inmunologíaRESUMEN
To understand how memory CD4 T cells are generated we have re-examined the requirements for continuing antigen stimulation in the generation and persistence of this population. We find that specific antigen is only required for a short period during the activation of naive CD4 T cells and is not required for memory generation from activated CD4 T cells or for persistence of resting memory cells generated by transfer of activated CD4 to adoptive hosts. Moreover, transfer of activated CD4 T cells to class-II-deficient hosts, indicates that TcR-class II major histocompatibility interaction is also unnecessary for either the transition from activated CD4 T cell to resting memory cells or for persistence over an eight-week period. Thus the signals regulating generation and maintenance of memory are fundamentally different from those which regulate the expansion of effector CD4 T-cell populations which include antigen itself and the CD4 T-cell autocrine cytokines induced by antigen.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Memoria Inmunológica/inmunología , Animales , HumanosRESUMEN
Aged naive CD4 T cells produce low levels of IL-2, leading to inefficient generation of effectors. The cells expand poorly, giving rise to few effectors with less activated phenotypes and reduced ability to produce cytokines. The aged cells also respond less vigorously in vivo. Addition of exogenous IL-2 or other gamma(c) receptor-signaling cytokines, restores expansion. However, only effectors generated in the presence of IL-2, are able to produce IL-2 in normal amounts and to become polarized to secrete Th2 cytokines. The defect in IL-2 production may be the only critical deficiency of aged naive CD4 T cells. Importantly, memory CD4 T cells generated from the IL-2 "restored" effectors are also deficient in IL-2 production, suggesting that a heritable change occurs during aging which effects production of IL-2 by resting naive and memory CD4 T cells, but not by optimally generated effectors.
Asunto(s)
Envejecimiento/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Interleucina-2/farmacología , Animales , Citocinas/biosíntesis , Citocinas/farmacología , Genes Codificadores de los Receptores de Linfocitos T , Memoria Inmunológica , Interleucina-2/biosíntesis , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Transgénicos , Fenotipo , Transducción de SeñalRESUMEN
The generation of memory T cells is critically important for rapid clearance and neutralization of pathogens encountered previously by the immune system. We have studied the kinetics of response and Ag dose requirements for proliferation and cytokine secretion of CD4+ memory T cells to examine whether there are qualitative changes which might lead to improved immunity. TCR Tg CD4+ T cells were primed in vitro and transferred into T cell-deficient hosts. After 6 or more weeks, the persisting T cells were exclusively small resting cells with a memory phenotype: CD44high CD62L+/- CD25-. Memory CD4 T cells showed a similar pattern of response as naive cells to peptide analogues with similar Ag dose requirements for IL-2 secretion. However, memory cells (derived from both Th2 and Th1 effectors) displayed faster kinetics of cytokine secretion, cell division, and proliferation, enhanced proliferation in response to low doses of Ag or peptide analogues, and production of IL-4, IL-5, and IFN-gamma. These results suggest there is a much more efficient response of CD4 memory T cells to Ag re-exposure and that the expanded functional capacity of memory cells will promote a rapid development of effector functions, providing more rapid and effective immunity.
Asunto(s)
Antígenos/inmunología , Memoria Inmunológica , Activación de Linfocitos , Subgrupos de Linfocitos T/inmunología , Secuencia de Aminoácidos , Animales , Trasplante de Médula Ósea/inmunología , Grupo Citocromo c/inmunología , Citocinas/biosíntesis , Relación Dosis-Respuesta Inmunológica , Femenino , Memoria Inmunológica/genética , Inmunofenotipificación , Interfase/inmunología , Cinética , Activación de Linfocitos/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Datos de Secuencia Molecular , Péptidos/inmunología , Quimera por Radiación , Subgrupos de Linfocitos T/metabolismoRESUMEN
Although B cells produce cytokines it is not known whether B cells can differentiate into effector subsets that secrete polarized arrays of cytokines. We have identified two populations of "effector" B cells (Be1 and Be2) that produce distinct patterns of cytokines depending on the cytokine environment in which the cells were stimulated during their primary encounter with antigen and T cells. These effector B cell subsets subsequently regulate the differentiation of naïve CD4+ T cells to TH1 and TH2 cells through production of polarizing cytokines such as interleukin 4 and interferon gamma. In addition, Be1 and Be2 cells could be identified in animals that were infected with pathogens that preferentially induce a Type 1 and Type 2 immune response. Together these results suggest that, in addition to their well defined role in antibody production, B cells may regulate immune responses to infectious pathogens through their production of cytokines.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Citocinas/biosíntesis , Subgrupos de Linfocitos T/inmunología , Animales , Subgrupos de Linfocitos B/citología , Diferenciación Celular , Citocinas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Nematospiroides dubius , Infecciones por Strongylida/inmunología , Subgrupos de Linfocitos T/citología , Células TH1/citología , Células TH1/inmunología , Células Th2/citología , Células Th2/inmunología , Toxoplasmosis Animal/inmunologíaRESUMEN
Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine with multiple roles in the immune system. To date, it has been difficult to develop a comprehensive picture of the effect of TGF-beta on T lymphocytes, because TGF-beta not only acts directly on T lymphocytes, but also acts indirectly by regulating the function of antigen-presenting cells. In early studies, it was mostly the inhibitory function of TGF-beta that was demonstrated; recently, however TGF-beta was recognized as an antiapoptotic survival factor for T lymphocytes. The outcome of the TGF-beta effect on T lymphocytes was shown to strongly depend on their stage of differentiation and on the cytokine milieu. TGF-beta cannot be classified as a classical Th1 or Th2 cytokine. However, recently the existence of the TGF-beta-producing Th3 subset was described which might play an important regulatory role during an immune response. A better understanding of the molecular mechanism of how TGF-beta inhibits or stimulates T lymphocytes will help to predict the complex functions of this cytokine.
Asunto(s)
Terapia de Inmunosupresión , Linfocitos T/efectos de los fármacos , Linfocitos T/fisiología , Factor de Crecimiento Transformador beta/farmacología , Animales , Humanos , Ratones , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
The factors required for the generation of memory CD4 T cells remain unclear, and whether there is a continuing requirement for antigen stimulation is critical to design of vaccine strategies. CD4 effectors generated in vitro from naïve CD4 T cells of mice efficiently gave rise to small resting memory cells after transfer to class II-deficient hosts, indicating no requirement for further antigen or class II recognition.
Asunto(s)
Antígenos de Histocompatibilidad Clase II/inmunología , Memoria Inmunológica , Subgrupos de Linfocitos T/inmunología , Células TH1/inmunología , Células Th2/inmunología , Traslado Adoptivo , Animales , División Celular , Citocinas/biosíntesis , Inmunización , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/citología , Células TH1/citología , Células Th2/citologíaRESUMEN
The basic helix-loop-helix protein, E2A, is required for proper early B lymphopoiesis. Specifically, in E2A-deficient mice, B-cell development is blocked at the progenitor stage prior to the onset of immunoglobulin (Ig) V(D)J recombination. Here, we demonstrate that E2A plays an additional role during peripheral B lymphopoiesis. Upon activation of primary mature B lymphocytes, both E2A protein levels and DNA-binding activity are induced. Furthermore, we show that mature B cells, expressing a dominant-negative E2A antagonist, proliferate normally in response to mitogenic signaling and appropriately express the early and late activation markers CD69, CD44, IgD and B220. However, in the absence of E2A activity, B lymphocytes are blocked in their ability to express secondary Ig isotypes. We demonstrate that the defect lies at the level of DNA rearrangements between the Ig switch regions. These data suggest that E2A is an essential target during B-cell activation and its induction is required to promote Ig class switch recombination.
Asunto(s)
Linfocitos B/inmunología , Proteínas de Unión al ADN/metabolismo , Isotipos de Inmunoglobulinas/genética , Región de Cambio de la Inmunoglobulina , Proteínas de Neoplasias , Animales , Antígenos CD/análisis , Antígenos de Diferenciación de Linfocitos T/análisis , Biomarcadores/análisis , Núcleo Celular/fisiología , Células Cultivadas , Citometría de Flujo , Secuencias Hélice-Asa-Hélice , Receptores de Hialuranos/análisis , Inmunoglobulina D/análisis , Proteínas Inhibidoras de la Diferenciación , Lectinas Tipo C , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa , Recombinación Genética/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Bazo/inmunología , Factores de Transcripción TCF , Células TH1/inmunología , Células Th2/inmunología , Proteína 1 Similar al Factor de Transcripción 7 , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción GenéticaRESUMEN
Development of effectors from naive CD4 cells occurs in two stages. The early stage involves activation and limited proliferation in response to T cell receptor (TCR) stimulation by antigen and costimulatory antigen presenting cells, whereas the later stage involves proliferation and differentiation in response to growth factors. Using a TCR-transgenic (Tg(+)) model, we have examined the effect of aging on effector generation and studied the ability of gamma(c) signaling cytokines to reverse this effect. Our results indicate that responding naive CD4 cells from aged mice, compared with cells from young mice, make less interleukin (IL)-2, expand poorly between days 3 to 5, and give rise to fewer effectors with a less activated phenotype and reduced ability to produce cytokines. When exogenous IL-2 or other gamma(c) signaling cytokines are added during effector generation, the Tg(+) cells from both young and aged mice proliferate vigorously. However, IL-4, IL-7, and IL-15 all fail to restore efficient effector production. Only effectors from aged mice generated in the presence of IL-2 are able to produce IL-2 in amounts equivalent to those produced by effectors generated from young mice, suggesting that the effect of aging on IL-2 production is reversible only in the presence of exogenous IL-2.
Asunto(s)
Envejecimiento/inmunología , Linfocitos T CD4-Positivos/inmunología , Citocinas/biosíntesis , Interleucina-2/farmacología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Linfocitos T/inmunología , Animales , Linfocitos T CD4-Positivos/citología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Células Cultivadas , Citocinas/farmacología , Antígenos H-2/inmunología , Interferón gamma/biosíntesis , Interferón gamma/farmacología , Interleucina-2/biosíntesis , Interleucina-4/biosíntesis , Interleucina-4/farmacología , Interleucina-5/biosíntesis , Interleucina-5/farmacología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Proteínas Recombinantes/farmacología , Linfocitos T/citología , Células TH1/inmunología , Células Th2/inmunologíaRESUMEN
The differentiation of Th cells is regulated at different points by antigen and by other factors in a complex fashion that allows impressive flexibility in the T cell response generated and enables close control at multiple points to prevent an unwanted response. Studies over the past two years have uncovered several principles of this regulation, including a new appreciation of the critical role of survival factors in determining the success of the immune response. New insights into the details of CD4(+) T cell regulation will provide important clues as to how immune responses are regulated, in particular the generation of effector responses and development of long-lived immunity.