Eliciting Th1 effector functions: A mechanism and role for innate amplification of the Th1 response during infection

Abstract

Innate and adaptive immunity have classically been considered as two distinct categories of cells and responses. Recently, however, an increasing appreciation for the dynamic interactions between these responses has developed. In this dissertation, this overlap is explored in the context of Th1 CD4 T cell production of IFN-γ (interferon-gamma) in response to innate stimuli. In particular, we first asked what triggers innate stimulation of Th1 cells, examining multiple ligands, infections and time points to show that this response occurred within broad contexts of intracellular infection. We then asked how T cells are able to recognize innate stimuli, focusing on whether the T cell intrinsic response relied upon direct LPS (lipopolysaccharide) recognition or indirect recognition of secondary signals. T cell intrinsic requirements were examined in mixed bone marrow chimeras that allowed T cells to be compared within the same environment. Upon demonstrating that the innate Th1 cell response required IL-18 (interleukin-18) receptor signaling, we next explored how T cell extrinsic PRRs (pattern recognition receptors) elicit effector functions through IL-18 secretion. Here, we showed a dual requirement for both TLR4 (toll-like receptor 4) and inflammasome pathways after LPS stimulation during Salmonella infection. The convergence of these pathways was required for increased IL-18 secretion, suggesting a dual level of control in production of such a proinflammatory cytokine. Finally, we asked whether the innate stimulation of Th1 cells is a required response pathway during clearance of Salmonella. Using Lck-cre x MyD88-loxP crossed mice, we demonstrated a deficiency in bacterial clearance in the absence of the signaling molecule MyD88 within T cells, which impairs the ability of Th1 cells to respond to IL-18, but not classical antigen stimulation. Together, this data suggests that the Th1 cell response utilizes a pathway of innate stimulation to amplify IFN-γ production under situations of severe inflammation, in which the classical adaptive response pathway may not be sufficient to mediate a strong and rapid response. Future work may explore additional infectious contexts, other CD4 T cell subsets, memory responses, and circumstances of immunopathology.