Type I IFN Modulates Innate and Specific Antiviral Immunity

Abstract

IFNs protect from virus infection by inducing an antiviral state and by modulating the immune response. Using mice deficient in multiple aspects of IFN signaling, we found that type I and type II IFN play distinct although complementing roles in the resolution of influenza viral disease. Both types of IFN influenced the profile of cytokines produced by T lymphocytes, with a significant bias toward Th2 differentiation occurring in the absence of responsiveness to either IFN. However, although a Th1 bias produced through inhibition of Th2 differentiation by IFN-γ was not required to resolve infection, loss of type I IFN responsiveness led to exacerbated disease pathology characterized by granulocytic pulmonary inflammatory infiltrates. Responsiveness to type I IFN did not influence the generation of virus-specific cytotoxic lymphocytes or the rate of viral clearance, but induction of IL-10 and IL-15 in infected lungs through a type I IFN-dependent pathway correlated with a protective response to virus. Combined loss of both IFN pathways led to a severely polarized proinflammatory immune response and exacerbated disease. These results reveal an unexpected role for type I IFN in coordinating the host response to viral infection and controlling inflammation in the absence of a direct effect on virus replication.

CD4 T Cell-Mediated Alloresistance to Fully MHC-Mismatched Allogeneic Bone Marrow Engraftment Is Dependent on CD40-CD40 Ligand Interactions, and Lasting T Cell Tolerance Is Induced by Bone Marrow Transplantation with Initial Blockade of this Pathway

“…CD8 ϩ CTL activation that is independent of CD40L/CD40 interactions occurs by both CD4 Thdependent (35) and CD4 cell-independent pathways (34, 36 -38) and in the absence of CD4-mediated APC conditioning (31-34, 39 -41). CD4 cell-independent APC activation can occur via LPR (42)(43)(44), C3R (45), Fc␥R (46), and CpG oligodinucleotides (45,(47)(48)(49), and these pathways are associated with the production of mediators of CD8 T cell activation, such as type I IFNs (44,46,50), TNF-␣ (51), IL-12 (52)(53)(54)(55)(56)(57), and IL-15 (58). Thus, we hypothesize that the failure to achieve engraftment in a proportion of animals receiving BMT with costimulatory blockade as the only immunosuppression may reflect such "bypass activation" of APCs due to exposure to microorganisms that cannot be controlled, and that this activation leads to the Th-independent activation of alloreactive recipient CD8 cells that then reject the donor marrow and prevent tolerance induction.…”

Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

“…2 Type I IFNs further activate the JAK-STAT signal transduction pathway to induce downstream proteins that inhibit viral replication and mediate the clearance of virus-infected cells, thereby driving the cellular antiviral response. [3][4][5] There are three major classes of PRRs, including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and nucleotide oligomerization domain-like receptors. 1 Viral RNAs are recognized by certain TLR family members, including TLR3, -7 and -8, and RLRs.…”

Immune system response to stress factors

“…viral infections. Subsequent IFN-a, IL-10 and IL-15 responses in tissues are usually the foundation of this Treg-mediated control action (Durbin et al, 2000); • the harnessing of pro-inflammatory cytokines by means of an array of humoral and cell-mediated control mechanisms (TNF-a soluble receptors, IL-1 decoy receptor, IL-1 receptor antagonist) (Kumar, 2003); • the local and systemic IFN-a response, which is likely to prevent a lethal septic shock at the onset of bacterial infections, as shown e.g. in the Schwartzman's reaction model (Billiau, 1988).…”