The Roles of IL-12 in Providing a Third Signal for Clonal Expansion of Naive CD8 T Cells

• Published in: The Journal of immunology (1950) 2002-12, Vol.169 (12), p.6842-6849
• Main Authors: Valenzuela, Javier, Schmidt, Clint, Mescher, Matthew
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - physiology; Animals; CD28 Antigens - physiology; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation - immunology; Cell Division - immunology; Cell Line; Clone Cells; Dose-Response Relationship, Immunologic; Drug Synergism; Injections, Intravenous; Interleukin-12 - administration & dosage; Interleukin-12 - metabolism; Interleukin-12 - physiology; Interleukin-2 - physiology; Interphase - immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Antigen, T-Cell - physiology; Receptors, Interleukin - biosynthesis; Receptors, Interleukin - genetics; Receptors, Interleukin-12; Receptors, Interleukin-2 - biosynthesis; Receptors, Interleukin-2 - genetics; RNA, Messenger - biosynthesis; Signal Transduction - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.169.12.6842

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.