The roles of IL-12 in providing a third signal for clonal expansion of naive CD8 T cells.
Stimulation of an effective in vitro or in vivo response by naive CD8 T cells requires three signals: TCR engagement, costimulation/IL-2, and a third signal that can be provided by IL-12. In addition to being required for acquisition of cytolytic function, IL-12 is required for optimal IL-2-dependent proliferation and clonal expansion. In experiments examining in vitro stimulation of naive CD8 T cells, IL-12 is shown to stimulate expression of the IL-2R alpha-chain (CD25) to much higher levels than are reached in response to just TCR and costimulation and/or IL-2. In addition, high CD25 expression is substantially prolonged in the presence of IL-12. As a consequence, the cells proliferate more effectively in response to low levels of IL-2. Examination of adoptively transferred TCR transgenic CD8 T cells responding to peptide Ag confirmed that IL-12 up-regulates CD25 in vivo, even when B7-mediated costimulation is largely blocked. TCR- and IL-2-dependent proliferation of CD8 T cells from mice deficient in CD25 was also found to increase in the presence of IL-12, indicating that CD25 up-regulation is not the only mechanism by which IL-12 increases clonal expansion of the cells. IL-2 and IL-12 both act to increase expression of both CD25 and the IL-12R, thus providing positive cross-regulation of receptor expression. These results suggest that when cross-priming dendritic cells present class I/Ag and costimulatory ligands, and produce IL-12, naive CD8 T cells will begin to produce IL-2 and both receptors will be optimally up-regulated to insure that an effective response is generated.
Valenzuela
Javier
J
Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Schmidt
Clint
C
Mescher
Matthew
M
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D018106:CD28 Antigens / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D002999:Clone Cells; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D007275:Injections, Intravenous; D018664:Interleukin-12 / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D007376:Interleukin-2 / Q000502:physiology; D007399:Interphase / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053707:Receptors, Interleukin-12; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*
D000276:Adjuvants, Immunologic; D018106:CD28 Antigens; D007376:Interleukin-2; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D015375:Receptors, Interleukin-2; D018664:Interleukin-12