Interferon lambda is required for interferon gamma-expressing NK cell responses but does not afford antiviral protection during acute and persistent murine cytomegalovirus infection

Abstract

Interferon lambda (IFNλ) is a group of cytokines that belong to the IL-10 family. They exhibit antiviral activities against certain viruses during infection of the liver and mucosal tissues. Here we report that IFNλ restricts in vitro replication of the β-herpesvirus murine cytomegalovirus (mCMV). However, IFNλR1-deficient (Ifnλr1-/-) mice were not preferentially susceptible to mCMV infection in vivo during acute infection after systemic or mucosal challenge, or during virus persistence in the mucosa. Instead, our studies revealed that IFNλ influences NK cell responses during mCMV infection. Ifnλr1-/- mice exhibited defective development of conventional interferon-gamma (IFNγ)-expressing NK cells in the spleen during mCMV infection whereas accumulation of granzyme B-expressing NK cells was unaltered. In vitro, development of splenic IFNγ+ NK cells following stimulation with IL-12 or, to a lesser extent, IL-18 was abrogated by IFNλR1-deficiency. Thus, IFNλ regulates NK cell responses during mCMV infection and restricts virus replication in vitro but is redundant in the control of acute and persistent mCMV replication within mucosal and non-mucosal tissues.

A genetic screen identifies a protective type III interferon response to Cryptosporidium that requires TLR3 dependent recognition

“…We note that administration of IFNλ was protective in Ifng -/- mice, suggesting that this protection does not require IFNγ. However, IFNλ has been shown to promote IFNγ production [ 44 ]. To examine this potential interaction further we tested the effect of IFNλ in mice lacking cells known to produce IFNγ in response to C .…”

“…Here we describe a second parasite detection mechanism that depends on TLR3 and produces a rapid IFNλ response that precedes the production of IFNγ by NK/ILCs and T cells. IFNλ has been shown to augment the IFNγ response of NK cells via a mechanism involving IL-12 [ 44 ]. However, loss of STAT1 exclusively in the enterocyte lineage led to almost a complete abrogation of the effects of IFNλ treatment ( Fig 4H ), arguing that the primary role of IFNλ is to act on the enterocyte.…”

Targeting IFN-λ Signaling Promotes Recovery from Central Nervous System Autoimmunity

“…IFNL may also influence Th2 cells in the CNS; however, we focused on Th1 and Th17 cells, as they have been strongly implicated in EAE pathogenesis (62). IFNL may also alter macrophage (13), NK cell (63), and neutrophil (61,64,65) polarization and cytokine production, as well as B cell differentiation (66).…”

Interferon-Independent Innate Responses to Cytomegalovirus

“…Type I and II IFNs are the best characterized in the context of HCMV and their induction, antiviral roles as well as the viral antagonism of these processes have been extensively reviewed (14)(15)(16)(17)(18)(19). A role for type III IFNs, in the innate response to HCMV and murine CMV (MCMV), whose pathogenesis closely parallels that of HCMV (20), has recently been elucidated (21)(22)(23)(24)(25)(26)(27).…”