Human Innate Lymphoid Cells in Influenza Infection and Vaccination

Abstract

Influenza is a highly contagious respiratory virus that causes mild to severe respiratory illness, as well as death, and remains a serious threat to human health. Annual vaccination is the most cost-effective way to control influenza; however, the vaccine does not provide protection against emerging strains with epidemic and pandemic potential. Several antivirals have been developed to treat influenza but there is a rapid emergence of antiviral resistant strains. Therefore, there is an urgent need to understand the virus and its interactions with the host immune system so that novel strategies can be developed for prophylactic and therapeutic interventions. Innate lymphoid cells (ILCs), a family of immune cells present in the peripheral circulation and in mucosal tissues, play an important role in regulation of tissue homeostasis, inflammation, and immunity. This review examines the current understanding and therapeutic potential of ILCs during influenza virus infection in humans.

FIG. 1:

The innate immune pathways (A) and the distribution of the ILCs at the mucosa of lungs (B) in response to influenza virus infection. (A) Infection of lung epithelial cells with influenza virus leads to the recognition of incoming viral genome and proteins by multiple host pathogen recognition receptors (PRRs). Ligand–PRR interaction leads to the secretion of type I and III IFNs, cytokines, and chemokines. The adaptive immune responses comprising humoral and cellular responses at both systemic and mucosal levels constitute the second line of defense against influenza viruses. The secreted cytokines and chemokines play a regulatory role in the cellular immune responses to IAVs. (B) The ILC subsets that play a role during influenza infection in lungs are illustrated and for simplicity the functions of the different subsets are emphasized. IAV infection of the lung epithelial cells results in the release various cytokines that can amplify the activation of ILC subsets. Red colored ILCs denote data derived from human studies and subsets found in human lungs or in peripheral circulation. Green denotes studies from murine models of influenza virus infection that further our understanding of these cell types in the lungs during influenza infection. Broken line indicates direct link is not established yet in either human or mice models of influenza virus infections. cDC, conventional dendritic cell; CTL, cytotoxic T-lymphocytes; dsRNA, double stranded RNA; IFN, interferon; IRF, interferon regulatory factor; MAVS, mitochondrial antiviral-signaling protein; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP, nucleotide-binding domain and leucine-rich-repeat-containing protein; pDC, plasmacytoid dendritic cell, RIG-I, retinoic acid-inducible gene-I; ssRNA, single stranded RNA; TLR, Toll-like receptor; vRNA, viral RNA; vRNP, viral ribonucleoprotein.

FIG. 2:

Developmental heterogeneity, subsets, effector cytokines and functions that define the ILC family in humans. ILCs initially originate from the HSC in the bone marrow that differentiates into CLPs in a multistep process in response to the transcription factors and cytokines to mature into six different classes. Different transcription factors and cytokines that mediate differentiation of the ILC subsets are included before the subset, and the distinguishing markers of each subset, and known functions of each subset are indicated to the right of each subset. Red indicates the subsets found in lungs or in the peripheral blood; green denotes subsets found in the peripheral blood or in the bone marrow; blue denotes subsets found in tissue (LTi, progenitor liver) or in tissue (ILC_Reg). AhR, aryl hydro-carbon receptor; CLP, common lymphoid progenitors; Eomes, Eomesodermin; GATA3, GATA binding protein 3; HSC, hematopoietic stem cell; LTi, lymphoid tissue inducer; RORα, RAR-related orphan receptor α; RORγt, RAR-related orphan receptor γt; T-bet, T-box transcription factor.