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The role of T-bet and eomesodermin in effector and memory CD8+ T cell differentiation

By Andrew Michael Intlekofer

Abstract

We sought to investigate the role of the T-box transcription factors, T-bet and eomesodermin (Eomes), in regulating the differentiation, homeostasis, and function of effector and memory CD8+ T cells. We found that T-bet and Eomes cooperatively control expression of genes required for cytotoxic effector function. CD8+ T cells deficient for both T-bet and Eomes fail to support host defense against lymphocytic choriomeningitis virus (LCMV) infection, lack the ability to kill target cells or secrete Type 1 cytokines, and undergo anomalous Type 17 differentiation. Upon infection with LCMV, mice with T cells lacking both T-bet and Eomes develop a CD8 + T cell-dependent, progressive wasting disease characterized by multi-organ neutrophilic inflammation. In addition to their essential role in effector differentiation, we found that T-bet and Eomes control the homeostasis of cytotoxic immune cells, as mice with compound mutations in the genes encoding T-bet and Eomes are nearly devoid of immune lineages dependent on interleukin 15 (IL-15), including memory CD8+ T cells. We determined that T-bet and Eomes are responsible for inducing enhanced expression of CD122, the receptor specifying IL-15 responsiveness. An examination of the differential contributions of T-bet and Eomes to CD8+ T cell differentiation revealed that T-bet preferentially drives terminal differentiation of effector-like cells at the expense of self-renewing memory cells. Thus, T-bet and Eomes appear to independently and semi-redundantly induce the genetic program necessary for Type 1 CD8+ T cell differentiation, whereas their unique functions may differentially contribute to acute versus long-term defense against intracellular pathogens

Topics: Biology|Molecular biology|Immunology
Publisher: ScholarlyCommons
Year: 2007
OAI identifier: oai:repository.upenn.edu:dissertations-7942
Provided by: ScholarlyCommons@Penn
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