Regulation of Effector and Memory Development of Human CD4+ T Cells by Interleukin 12 and Type I Interferon

Innate cytokines induced at the onset of infection regulate the development of adaptive immune responses such as CD4+ T helper cell development. For instance, the innate cytokines interleukin 12 (IL-12) and type I interferon (IFN-alpha/beta) are produced in response to intracellular bacterial and viral infections. While the effects of IL-12 on CD4+ T cell differentiation are relatively well-understood, the role of IFN-alpha/beta, despite extensive study, has remained controversial. The present work seeks to clarify the effects of IFN-alpha/beta on CD4+ T cell development, effector functions, and memory generation. Previous reports had suggested that IFN-alpha, like IL-12, could promote Th1 development in human CD4+ T cells. However, my work demonstrates that IFN-alpha is insufficient to induce Th1 differentiation because of an inability to maintain stable STAT4 phosphorylation or T-bet expression. Furthermore, IL-12, but not IFN-alpha, induces the secretion of IFN-gamma and TNF-alpha from human CD4+ T cells. These two cytokines, in addition to promoting bacterial clearance, can directly participate in antiviral immunity via a signaling pathway which involves the type I IFN receptor. Finally, a combination of IL-12 and IFN-alpha influences memory CD4+ T cell function by strongly inducing IL-2 secretion from a subset of cells in a T-bet-independent manner. These IL-2-producing cells demonstrate both phenotypic and functional characteristics of long-lived and pluripotent central memory. Taken together, these data provide a new understanding of the role of innate cytokines in shaping adaptive CD4+ T cell responses. Given the numerous medical uses of IFN-alpha/beta, these findings could have a broad impact on the design of vaccines and antiviral therapeutics.

Author dc:creator

• Davis, Ann Marie

Contributors dc:contributor

• Farrar, J. David

• CD4-Positive T-Lymphocytes
• Immunologic Memory
• Interferon-alpha

Language dc:language

en

Identifier

759853519

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/645