Date of Award
Doctor of Philosophy (PhD)
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.
Rahman, Adeeb H., "DEFINING A T CELL-INTRINSIC ROLE FOR MYD88 DURING LCMV INFECTION" (2009). Publicly accessible Penn Dissertations. Paper 37.