A Unique Mechanism for Innate Cytokine Promotion of T Cell Responses to Viral Infections

Abstract

The kinetics of CD8 T cell IFN-γ responses as they occur in situ are defined here during lymphocytic choriomeningitis virus (LCMV) infections, and a unique mechanism for the innate cytokines IFN-αβ and IL-18 in promoting these responses is defined. Infections of mice with Armstrong or WE strains of LCMV induced an unexpectedly early day 4 IFN-γ response detectable in serum samples and spleen and liver homogenates. Production of IFN-γ was MHC class I/CD8 dependent, but did not require IL-12, NK cells, TCR-γδ T cells, MHC class II, or CD4 T cells. Peak response required specific Ag recognition, as administration of antagonist peptide partially impaired day 4 IFN-γ induction, and viral peptide stimulation enhanced CD8 T cell IFN-γ expression in culture. The IFN-γ response was associated with IL-18 and IFN-αβ expression. Furthermore, both factors augmented peptide-driven IFN-γ production in culture, and mice lacking IL-18 or IFN-αβ functions had reduced day 4 IFN-γ. Collectively, these results demonstrate that during viral infections, there is a dramatic in vivo CD8 T cell response preceding maximal expansion of these cells, and that the mechanism supporting this response is dependent on endogenous innate cytokines. Because stimulation by microbial products is linked to innate cytokine expression, the studies also suggest a pathway for precisely limiting T cell functions to times of need.

Murine γ-Herpesvirus-68-Induced IL-12 Contributes to the Control of Latent Viral Burden, but Also Contributes to Viral-Mediated Leukocytosis

“…Furthermore, these IL-12-deficient mice were still capable of producing IFN-␥ and generating a Th1 response against this viral infection. Similar results were observed when IL-12p40 Ϫ/Ϫ mice were infected with lymphocytic choriomeningitis virus (61,62). In these models of viral infection, it is not altogether clear which IL-12-independent mechanisms account for the antiviral responses.…”

Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

“…Notably, IFN responses induced by virus infection are enhanced in the presence of IL-18 (ref. 47). We therefore cannot exclude a role for these cytokines in the delayed diabetes induction found in our Myd88 -/-experiments.…”

Direct Interferon-γ Signaling Dramatically Enhances CD4+ and CD8+ T Cell Memory

“…However, virus-specific naive T cells in vivo encounter their cognate Ag during infection, in the presence of inflammatory signals, and a number of recent studies suggest that these inflammatory events can alter the intrinsic developmental pathway. Type I and type II IFNs appear to play important roles in these early regulatory events (3,4). In the absence of the type I IFN receptor, the acute CD8 ϩ T cell response is dramatically reduced (5); this is true also for CD4 ϩ T cell responses, although the effects seem to vary depending on the nature of the infecting microbe (6).…”