Defining a T Cell-Intrinsic Role for MyD88 During LCMV infection

Loading...
Thumbnail Image
Degree type
Doctor of Philosophy (PhD)
Graduate group
Immunology
Discipline
Subject
T cell
toll-like receptor
survival
expansion
virus
Immunity
Funder
Grant number
License
Copyright date
Distributor
Related resources
Contributor
Abstract

Immune activation through Toll-like receptors (TLRs) has historically been considered to be a characteristic of cells of the innate, rather than adaptive immune system. Recent studies have challenged this paradigm by demonstrating that TLRs are also expressed on T lymphocytes and that TLR ligands can directly co-stimulate T cell responses in vitro. However, the physiological relevance of these findings during in vivo immune responses was unclear. Mice lacking the critical TLR-adapter protein, myeloid differentiation protein 88 (MyD88), have increased susceptibility to numerous pathogens, highlighting the importance of TLRs in host defense. While the immune impairments associated with MyD88-deficiency have generally been attributed to the importance of MyD88 in regulating innate immune responses, in light of the studies showing that TLRs can directly stimulate T cells, we hypothesized that they may also reflect a direct role for MyD88 in T cells. In this work, we use lymphocytic choriomeningitis virus (LCMV) as a model infection to examine the role of MyD88 in regulating antiviral T cell responses. Using a series of adoptive cell transfer and bone marrow chimera experiments, we identify a critical, but previously unappreciated, T-cell intrinsic role for MyD88 in regulating the survival and expansion of LCMV-specific effector T cells during acute viral infection. Using a system to inducibly delete MyD88 we also show that, while naïve T cells critically depend on MyD88-dependent signals for their expansion, virus-specific memory T cells do not require MyD88 for their differentiation, maintenance or reactivation in response to secondary infection. Overall, our findings broaden the importance of MyD88 in T cells, support a shift in the dogma that restricts the role MyD88 to cells of the innate immune system, and may have significant implications for understanding the signals that control T cell survival during inflammatory immune responses.

Advisor
Laurence Turka
Date of degree
2009-12-22
Date Range for Data Collection (Start Date)
Date Range for Data Collection (End Date)
Digital Object Identifier
Series name and number
Volume number
Issue number
Publisher
Publisher DOI
Journal Issue
Comments
Recommended citation