MyD88 is critical for the development of innate and adaptive immunity during acute lymphocytic choriomeningitis virus infection

Abstract

We investigated the roles of Toll-like receptor 2 (TLR2) and myeloid differentiation factor 88 (MyD88) in the course of a lymphocytic choriomeningitis virus (LCMV) infection and revealed the following: (i) studies of transfected cells and murine peritoneal macrophages demonstrated that TLR2 and MyD88 are essential for the initial pro-inflammatory cytokine response (human IL-8, mouse IL-6) to LCMV; (ii) TLR2 knockout (KO) mice and MyD88 KO mice challenged with LCMV produced less IL-6 and monocyte chemotactic protein-1 in the serum than wild-type mice; (iii) in contrast to inflammatory cytokines, the production of type 1 IFN (IFN-a) in response to LCMV was MyD88 independent; (iv) MyD88 plays an essential role in antiviral CD8 + T cell responses, CD8 + T cells in MyD88 KO mice were defective in their expression of intracellular antiviral cytokines; and (v) the failure of MyD88 KO mice to activate CD8 + T cells was accompanied by persistent viral infection in MyD88 KO mice. We demonstrate that TLR-mediated responses are important in the innate immune response to LCMV and that MyD88 is essential for the control of the LCMV infection and the maturation/activation of virus-specific CD8 + T cells.

Virus-induced polyclonal B cell activation improves protective CTL memoryvia retained CD27 expression on memory CTL

“…Therefore, the difference between primary and secondary expansion may be explained by the kinetics of the antigen elimination. Whereas in primary LCMV infection the high antigen load and the widespread distribution may compensate for the lack of CD27, memory CTL expand rapidly and contain the infectious inoculum during reinfection before high antigen levels, widespread infection and general inflammation including the release of inflammatory cytokines are achieved [32]. Surprisingly, comparable to HIV and EBV infection in humans [10,13,33], memory CTL retained CD27 surface expression after infection with LCMV, whereas memory CTL after infection with recombinant vaccinia virus or after immunization with a tumor cell line converted to CD27 lo/neg memory CTL.…”

MyD88 Is Pivotal for the Early Inflammatory Response and Subsequent Bacterial Clearance and Survival in a Mouse Model of Chlamydia pneumoniae Pneumonia

“…Whereas previous studies have demonstrated no defects in MyD88-deficient mice in the total number of CD4 ϩ and CD8 ϩ T cells, and in their ability to produce IFN-␥ after nonspecific activation (27), more recent studies have shown that MyD88-deficient mice have defects in their CD8 ϩ T cell response to acute viral infections such as lymphocytic choriomeningitis virus (LCMV) (28,29). Hence, our data are most consistent with the interpretation that the major reason MyD88 Ϫ/Ϫ mice could not clear the pathogen from their lungs and developed a chronic inflammation was that an early localized proinflammatory response was lacking, PMNs were not recruited, and recruitment of CD8 ϩ T cells into the infected lungs was delayed, that these factors conspired to allow the bacteria to flourish in the lungs of MyD88 Ϫ/Ϫ mice, and that continued inability to clear the pathogen led to the delayed but intense lung inflammation and increased mortality.…”

Complement-Dependent Enhancement of CD8+ T Cell Immunity to Lymphocytic Choriomeningitis Virus Infection in Decay-Accelerating Factor-Deficient Mice

“…By analogy to LPS-stimulated events, it may be speculated that a similar synergistic interaction between complement and TLR occurred in LCMV-infected Daf-1 Ϫ/Ϫ mice, which promoted dendritic cell maturation and/or T cell priming through elevated inflammatory cytokine production and adhesion/costimulatory molecule expression. Relevant to this hypothesis, previous work by others has shown that LCMV-driven innate and CD8 ϩ T cell immunity in mice was dependent on TLR2 and the obligatory TLR signaling adaptor molecule MyD88 (44).…”