RESUMO
Autocrine IFN-γ signaling is important for CD4 differentiation to Th1 effector cells, but it has been unclear whether it contributes to CD8 T cell differentiation. We show in this paper that naive murine CD8 T cells rapidly and transiently produce low levels of IFN-γ upon stimulation with Ag and B7-1, with production peaking at â¼8 h and declining by 24 h. The autocrine IFN-γ signals for upregulation of expression of T-bet and granzyme B and induces weak cytolytic activity and effector IFN-γ production. IFN-α acts synergistically with IFN-γ to support development of strong effector functions, whereas IL-12 induces high T-bet expression and strong function in the absence of IFN-γ signaling. Thus, IFN-γ is not only an important CD8 T cell effector cytokine, it is an autocrine/paracrine factor whose contributions to differentiation vary depending on whether the response is supported by IL-12 or type I IFN.
Assuntos
Comunicação Autócrina/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Interferon-alfa/fisiologia , Interferon gama/fisiologia , Transferência Adotiva/métodos , Animais , Comunicação Autócrina/genética , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Células Cultivadas , Interferon gama/deficiência , Interferon gama/genética , Interleucina-12/fisiologia , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Comunicação Parácrina/genética , Comunicação Parácrina/imunologia , Proteínas com Domínio T/biossíntese , Proteínas com Domínio T/fisiologia , Regulação para Cima/genética , Regulação para Cima/imunologiaRESUMO
A third signal that can be provided by IL-12 or type I IFN is required for differentiation of naive CD8 T cells responding to Ag and costimulation. The cytokines program development of function and memory within 3 days of initial stimulation, and we show here that programming involves regulation of a common set of approximately 355 genes including T-bet and eomesodermin. Much of the gene regulation program is initiated in response to Ag and costimulation within 24 h but is then extinguished unless a cytokine signal is available. Histone deacetylase inhibitors mimic the effects of IL-12 or type I IFN signaling, indicating that the cytokines relieve repression and allow continued gene expression by promoting increased histone acetylation. In support of this, increased association of acetylated histones with the promoter loci of granzyme B and eomesodermin is shown to occur in response to IL-12, IFN-alpha, or histone deacetylase inhibitors. Thus, IL-12 and IFN-alpha/beta enforce in common a complex gene regulation program that involves, at least in part, chromatin remodeling to allow sustained expression of a large number of genes critical for CD8 T cell function and memory.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Montagem e Desmontagem da Cromatina/imunologia , Regulação da Expressão Gênica/imunologia , Memória Imunológica/genética , Interferon Tipo I/fisiologia , Interleucina-12/fisiologia , Acetilação , Animais , Apresentação de Antígeno , Diferenciação Celular , Histonas/metabolismo , Camundongos , Proteínas com Domínio T/genéticaRESUMO
CD8 T cells specific for self-antigens are present in the peripheral lymphoid system and can contribute to autoimmunity or transplant rejection. Whether recognition of Ag leads to full activation, or to induction of tolerance, depends upon availability of cytokine at critical stages of the response. Signals provided by IL-12 and/or IFN-alpha/beta are required for activation of naïve CD8 T cells, and IL-2 is needed to sustain and further expand the effector cells if Ag persists. These critical signaling requirements provide new insights into the factors that regulate the CD8 T cell contributions to development of autoimmunity or rejection of transplants.
Assuntos
Antígenos CD28/fisiologia , Tolerância Imunológica , Imunidade Celular/imunologia , Ativação Linfocitária , Subpopulações de Linfócitos T/imunologia , Animais , Antígenos CD28/imunologiaRESUMO
Stimulation of naïve CD8+ T cells with antigen and costimulation results in proliferation and weak clonal expansion, but the cells fail to develop effector functions and are tolerant long term. Initiation of the program leading to the strong expansion and development of effector functions and memory requires a third signal that can be provided by interleukin-12 (IL-12) or interferon-alpha (IFN-alpha). CD4+ T cells condition dendritic cells (DCs) to effectively present antigen to CD8+ T cells, and this conditioning involves, at least in part, CD40-dependent upregulation of the production of these signal 3 cytokines by the DCs. Upon being fully activated, the cytotoxic T lymphocytes develop activation-induced non-responsiveness (AINR), a form of split anergy characterized by an inability to produce IL-2 to support continued expansion. If antigen remains present, IL-2 provided by CD4+ T cells can reverse AINR to allow further expansion of the effector population and conversion to responsive memory cells following antigen clearance. If IL-2 or potentially other proliferative signals are not available, persistent antigen holds cells in the AINR state and prevents the development of a responsive memory population. Thus, in addition to antigen and costimulation, CD8+ T cells require cytokine signals at distinct stages of the response to be programmed for optimal generation of effector and memory populations.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Humanos , Interferon-alfa/imunologia , Interleucina-12/imunologia , Transdução de Sinais/imunologiaRESUMO
In this study, we show that IFN-alpha beta can have a direct role in linking innate and adaptive responses by providing the "third signal" needed by naive CD8 T cells responding to Ag and costimulatory ligands. Stimulation of CD8 T cells in the absence of a third signal leads to proliferation, but clonal expansion is limited by poor survival and effector functions do not develop. We show that IFN-alpha beta can provide the third signal directly to CD8 T cells via a STAT4-dependent pathway to stimulate survival, development of cytolytic function, and production of IFN-gamma. Provision of the third signal by either IFN-alpha beta or IL-12 results in regulation of the expression of a number of genes, including several that encode proteins critical for effector function.