Title

The cellular and molecular regulation of T helper responses in murine neonates

Date of Award

2005

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Microbiology and Immunology

First Committee Member

Becky Adkins, Committee Chair

Abstract

Immune responses in murine neonates are typically Th2-biased. This is characterized by high-level IL-4 production at all phases of the immune response and poor Th1 memory responses. While the processes controlling adult T helper (Th) cell differentiation and function have been studied extensively, the regulation of these processes in neonatal cells is poorly understood. Therefore, the overall goal of this project was to uncover some of the molecular mechanisms contributing to the Th2 dominance of neonatal immunity.DNA methylation represses Th2 cytokine expression in adult CD4 + T cells. One aim of this project was to determine the role of DNA methylation in regulating neonatal Th2 responses. During the course of these studies, it was found that murine neonatal CD4+ cells may be uniquely pre-programmed for rapid Th2 effector-like function. Early Th2 function in neonates arose from a small population of IL-4-secreting cells, did not require cell cycle entry, and was unaffected by pharmacologic DNA demethylation. Direct CpG methylation analyses in resting neonatal cells revealed pre-existing hypomethylation at a key Th2 cytokine regulatory region, termed conserved noncoding sequence 1 (CNS-1). Robust Th2 function and increased CNS-1 demethylation persisted in neonatal Th2 effectors. Thus, neonatal CD4+ cells possess several unique properties that could predispose them toward rapid, high-level Th2 function.Th cell differentiation and function are governed by the transcription factors STAT6 and T-bet. Each of these mediators positively regulates its own Th lineage and negatively regulates the opposing lineage in adult CD4 + cells, yet their effects in neonatal cells are unknown. Another goal of this project was to determine the role of these transcription factors in neonatal Th cells. The absence of STAT6 and T-bet had similar qualitative effects on the development of effector function in neonates and adults. However, Th1 memory responses were more severely inhibited by STAT6 signals during the neonatal period than in adult life. These findings demonstrate that STAT6 is central in shaping the neonatal Th2 bias by promoting Th2 responses and concomitantly strongly downregulating Th1 function. In addition, they indicate that these key regulators of Th cell development and function are already established in early life.

Keywords

Health Sciences, Immunology

Link to Full Text

http://access.library.miami.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3198732