Influenza-Activated ILC1s Contribute to Antiviral Immunity Partially Influenced by Differential GITR Expression

Abstract

Innate lymphoid cells (ILCs) represent diversified subsets of effector cells as well as immune regulators of mucosal immunity and are classified into group 1 ILCs, group 2 ILCs, and group 3 ILCs. Group 1 ILCs encompass natural killer (NK) cells and non-NK ILCs (ILC1s) and mediate their functionality via the rapid production of IFN-γ and TNF-α. The current knowledge of ILC1s mainly associates them to inflammatory processes. Much less is known about their regulation during infection and their capacity to interact with cells of the adaptive immune system. The present study dissected the role of ILC1s during early influenza A virus infection, thereby revealing their impact on the antiviral response. Exploiting in vitro and in vivo H1N1 infection systems, a cross-talk of ILC1s with cells of the innate and the adaptive immunity was demonstrated, which contributes to anti-influenza immunity. A novel association of ILC1 functionality and the expression of the glucocorticoid-induced TNFR-related protein (GITR) was observed, which hints toward a so far undescribed role of GITR in regulating ILC1 responsiveness. Overexpression of GITR inhibits IFN-γ production by ILC1s, whereas partial reduction of GITR expression can reverse this effect, thereby regulating ILC1 functionality. These new insights into ILC1 biology define potential intervention targets to modulate the functional properties of ILC1s, thus contributing toward the development of new immune interventions against influenza.

Tissue‐resident innate immunity in the lung

“…Despite only representing a minor fraction of total ILCs in the lung, 58,64 there is evidence that ILC1s play a role in immunosurveillance and infection control. In mice infected with H1N1 influenza virus, ILC1s become activated and produce interferon-c (IFN-c) and tumour necrosis factor-a as early as day 3, suggesting a role in initiating the early response to infection; 65 and transfer of ILC1s to lymphocyte-deficient mice (Rag2 À/À cC À/À ), reduces viral titres in the lung. The concept of ILC1s as important early producers of IFN-c in tissue is supported by a recent study showing depletion of ILC1s from Tcell-deficient mice increased titres of another respiratory virus, Sendai virus in the lung following nasal challenge.…”

Innate lymphoid cells in lung infection and immunity

“…ILC1 have also been studied in the context of viral influenza infection (Figure ). Two days post‐infection an increase in IFN‐γ‐producing ILC1 was observed in lung tissue .…”

“…ILC1 have also been studied in the context of viral influenza infection (Figure ). Two days post‐infection an increase in IFN‐γ‐producing ILC1 was observed in lung tissue . Furthermore, a memory‐like ILC1 population generated after primary influenza infection and residing in the liver was shown to be protective in in vivo adoptive transfer experiments of infected Rag1 −/− mice …”

Enteric bacteria induce IFNγ and Granzyme B from human colonic Group 1 Innate Lymphoid Cells

“…Group 1 Innate Lymphoid Cells (ILCs), which include the well-studied Natural Killer (NK) cells and the more recently discovered ILC1 subset, have an established role in anti-viral immunity, 1,2 but are also important in anti-bacterial immunity 3 particularly in the gastrointestinal tract. 4,5 Within the gut mucosa, one mechanism by which Group 1 ILCs control bacterial infection is through the production of IFNγ.…”