Activation of virus-specific CD8+ T cells by lipopolysaccharide-induced IL-12 and IL-18.
Virus-specific T cells represent a hallmark of Ag-specific, adaptive immunity. However, some T cells also demonstrate innate functions, including non-Ag-specific IFN-gamma production in response to microbial products such as LPS or exposure to IL-12 and/or IL-18. In these studies we examined LPS-induced cytokine responses of CD8(+) T cells directly ex vivo. Following acute viral infection, 70-80% of virus-specific T cells will produce IFN-gamma after exposure to LPS-induced cytokines, and neutralization experiments indicate that this is mediated almost entirely through production of IL-12 and IL-18. Different combinations of these cytokines revealed that IL-12 decreases the threshold of T cell activation by IL-18, presenting a new perspective on IL-12/IL-18 synergy. Moreover, memory T cells demonstrate high IL-18R expression and respond effectively to the combination of IL-12 and IL-18, but cannot respond to IL-18 alone, even at high cytokine concentrations. This demonstrates that the synergy between IL-12 and IL-18 in triggering IFN-gamma production by memory T cells is not simply due to up-regulation of the surface receptor for IL-18, as shown previously with naive T cells. Together, these studies indicate how virus-specific T cells are able to bridge the gap between innate and adaptive immunity during unrelated microbial infections, while attempting to protect the host from cytokine-induced immunopathology and endotoxic shock.
Raué
Hans-Peter
HP
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA.
Brien
James D
JD
Hammarlund
Erika
E
Slifka
Mark K
MK
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D004357:Drug Synergism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000502:physiology*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D053727:Interleukin-18 Receptor alpha Subunit; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D021122:Protein Subunits / Q000096:biosynthesis / Q000502:physiology; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000502:physiology; D053724:Receptors, Interleukin-18; D012772:Shock, Septic / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D008070:Lipopolysaccharides; D021122:Protein Subunits; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma