RESUMEN
Exposure of naive CD8 T cells to the synergistic combination of interleukin (IL)-7 and IL-21 enables them to respond strongly to subsequent antigen stimulation. Mechanisms underlying the increased antigen responsiveness of such cytokine-primed CD8 T cells remain unknown. In this study, we showed that a brief exposure of <24 h to IL-7 and IL-21 is sufficient enough to sensitize naive P14 T-cell receptor (TCR) transgenic CD8 T cells to respond to limiting quantities of antigen, resulting in increased proliferation, interferon-gamma secretion and antigen-specific cytolytic activity. Cytokine-induced increase in TCR responsiveness occurs even in the absence of costimulatory signals. Cytokine priming upregulates the expression of the gamma(c) chain and increases IL-2 production after antigen stimulation, thus enhancing autocrine stimulation. Notably, cytokine priming induces a rapid and profound downmodulation of CD5, implicated in the negative regulation of TCR signaling, by induction of the transcriptional repressor E47. These findings show that increased antigen responsiveness of cytokine-primed CD8 T cells results from the modulation of multiple cell-surface molecules, which influence cytokine receptor and TCR signaling.
Asunto(s)
Antígenos CD5/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Regulación hacia Abajo/efectos de los fármacos , Interleucina-7/farmacología , Interleucinas/farmacología , Adyuvantes Inmunológicos/farmacología , Animales , Western Blotting , Proliferación Celular , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Interleucina-7/metabolismo , Interleucinas/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Activation of naive T cells by antigen requires signaling via the T-cell receptor (TCR) and co-stimulatory receptors. However, in response to homeostatic pressure, T lymphocytes undergo cytokine-driven proliferation without overt antigen stimulation. Homeostatic expansion is more pronounced in the CD8+ T-cell compartment, with memory CD8+ T cells showing intense proliferation resulting from increased responsiveness to IL-15. On the other hand, naive CD8+ T cells require IL-7 and MHC-I to undergo homeostatic expansion, implying the requirement for a basal level of TCR signaling. Probably because of this strict requirement for MHC, earlier reports on antigen-independent stimulation of naive human CD8+ T cells by inflammatory cytokines did not receive much attention. Recently, we and others have shown that naive murine CD8+ T cells undergo proliferation following synergistic simulation by inflammatory cytokines. Such cytokine-driven, antigen-independent activation also "sensitizes" or "primes" naive CD8+ T cells, enabling them to respond robustly to limiting concentrations of cognate antigens, produce effector cytokines abundantly, and display potent cytolytic activity. We propose that cytokine synergy, which induces antigen-independent activation and priming of naive CD8+ T cells, may significantly contribute to the transition from innate to adaptive immune response and to inadvertent activation of autoreactive CD8+ T cells.
Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Homeostasis/inmunología , Interleucina-7/inmunología , Activación de Linfocitos , Subgrupos de Linfocitos T/metabolismo , Animales , Antígenos/inmunología , Autoinmunidad , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Humanos , Inmunidad Innata , Inflamación , Interleucina-7/metabolismo , Ratones , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunologíaRESUMEN
The recessive lyp allele, which harbors a defective gimap5 (GTPase of immunity-associated nucleotide binding protein 5) gene, causes spontaneous apoptosis of T lymphocytes in the biobreeding diabetes-prone strain of rats. Mechanisms underlying the pro-survival function of GIMAP5 remain unclear. In this study, we show that gimap5(lyp/lyp) T cells display diminished calcium flux in response to thapsigargin or signaling via the T cell antigen receptor. This defect is manifested in mature single positive thymocytes, where the survival defect first occurs. We also show that GIMAP5 deficiency does not affect the thapsigargin-induced calcium release from the intracellular stores but impairs subsequent calcium entry across the plasma membrane. Our findings suggest that GIMAP5 is an important regulator of calcium response in T lymphocytes and impaired calcium signaling might underlie spontaneous apoptosis of gimap5(lyp/lyp) T cells.