The innate and adaptive immune systems are often considered independent. The innate arm is generalized as broad and non-specific, while the adaptive arm more slowly generates a targeted response against a particular antigen and develops memory. These complementary mechanisms are in fact intertwined, as exemplified by non-classical T cells. Unlike conventional T cells, which are restricted by MHC class Ia and II molecules, non-classical T cells recognize MHC class Ib and MHC class I-like molecules. These cells bridge the innate and adaptive immune systems because they often have rapid effector functions and recognize unique types of antigens. They also frequently require distinct transcription factors and signaling events during development. Additionally, non-classical T cells are becoming acknowledged as novel participants during microbial infections. The work presented here explores the development and functions of non-classical T cells, including invariant natural killer T (iNKT) cells and MHC class Ib-restricted CD8+ T cells. First, we show that SHIP1, a negative regulator of the cell cycle and survival, does not participate in iNKT cell development or proliferation, but instead enhances cytokine production. We also examine the participation of non-classical T cells during murine cytomegalovirus (MCMV) infection, which is used as a model to study human CMV infections. IL-12 is necessary for the appropriate activation of iNKT cells to MCMV. However, we also find that there is organ specificity in the requirement for MyD88, which is downstream of the TLR/IL-1R/IL-18R family. Splenic iNKT cells are hyporesponsive in the absence of MyD88 signaling, whereas hepatic iNKT cells are unaffected. In contrast, we demonstrate that MHC class Ib-restricted CD8+ T cells robustly respond in an MCMV-dependent manner, rather than through inflammatory cytokines. Strikingly, these cells form memory, are sufficient to protect immunocompromised mice from MCMV-induced lethality, and are a heterogeneous population comprised of Qa-1- and non-Qa-1-restricted cells. Altogether, these studies contribute to our understanding of non-classical T cell development and functions, as well as their unique roles during viral infection.
Anderson, Courtney Kay,
"Non-classical T cell development and their functions during murine cytomegalovirus"
(2018).
Pathobiology Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.26300/nbyw-b031
