Reciprocal Regulation of CD4+ and CD8+ T Lymphocyte Effector and Memory Fates by Interleukin 12 and Type 1 Interferon




Ramos, Hilario Jose

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Cytokine signaling networks play an important role in bridging the innate and adaptive immune responses. For example, the innate cytokines Interleukin-12 (IL-12) and type I interferon (IFN-a/b) are induced to high levels by intracellular bacterial and viral infections and have been shown to promote adaptive T lymphocyte responses to infection. While the role for IL-12 on the development of T lymphocyte effector responses has been well characterized, the exact role for IFN-a/b on these responses has been controversial. Therefore, the present study set forth to characterize the distinct roles for IL-12 and IFN-a/b on the development of effector and memory responses in human CD4+ and CD8+ T cells. My work has found that IL-12 drives the development of effector CD4+ and CD8+ T cells. In contrast, IFN-a/b was incapable of promoting these responses and this was due to a difference in the kinetics of activation of two downstream transcription factors STAT4 and T-bet. Further examination of CD8+ T cells revealed a distinct role for IFN-a/b in the development of a population of central memory T cells (TCM). Alternatively, IL-12 drove the development of effector memory cells (TEM). The variegated development of TCM and TEM was dictated by differential cytokine receptor expression and further, the strength of primary T cell receptor (TCR) activation determined the responsiveness to cytokine polarization. Finally, these studies uncovered a novel role for CD8+ T cell licensing of CTL activity through the costimulatory CD27/CD70 pathway. Therefore, taken together, these findings support a novel model in which TCR activation and costimulation act to shape the ability for IL-12 and IFN-a/b to differentially program the development of distinct classes of effector and memory CD8+ T lymphocytes. These studies have direct bearing on the design and development of effective therapeutics and vaccines and demonstrate a new understanding on the modulation of the adaptive immune response to intracellular infection.

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