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1.
Immunol Cell Biol ; 88(4): 451-60, 2010.
Article in English | MEDLINE | ID: mdl-20065997

ABSTRACT

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.


Subject(s)
CD5 Antigens/metabolism , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Down-Regulation/drug effects , Interleukin-7/pharmacology , Interleukins/pharmacology , Adjuvants, Immunologic/pharmacology , Animals , Blotting, Western , Cell Proliferation , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Interleukin-7/metabolism , Interleukins/metabolism , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Transgenic
2.
Crit Rev Immunol ; 29(3): 219-39, 2009.
Article in English | MEDLINE | ID: mdl-19538136

ABSTRACT

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.


Subject(s)
CD8-Positive T-Lymphocytes/metabolism , Homeostasis/immunology , Interleukin-7/immunology , Lymphocyte Activation , T-Lymphocyte Subsets/metabolism , Animals , Antigens/immunology , Autoimmunity , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Cell Proliferation , Humans , Immunity, Innate , Inflammation , Interleukin-7/metabolism , Mice , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Signal Transduction/immunology , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology
3.
Mol Immunol ; 46(6): 1256-9, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19007993

ABSTRACT

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.


Subject(s)
Calcium Signaling/immunology , GTP-Binding Proteins/immunology , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/immunology , Animals , Animals, Genetically Modified , Calcium Signaling/physiology , Cell Membrane/physiology , GTP-Binding Proteins/genetics , In Vitro Techniques , Rats , T-Lymphocytes/drug effects , Thapsigargin/pharmacology , Thymus Gland/cytology
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