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Review
. 2012 Mar 9;12(4):295-305.
doi: 10.1038/nri3166.

Regulating the adaptive immune response to respiratory virus infection

Thomas J Braciale  1 , Jie Sun, Taeg S Kim
Affiliations
Review

Regulating the adaptive immune response to respiratory virus infection

Thomas J Braciale et al. Nat Rev Immunol. .

Abstract

Recent years have seen several advances in our understanding of immunity to virus infection of the lower respiratory tract, including to influenza virus infection. Here, we review the cellular targets of viruses and the features of the host immune response that are unique to the lungs. We describe the interplay between innate and adaptive immune cells in the induction, expression and control of antiviral immunity, and discuss the impact of the infected lung milieu on moulding the response of antiviral effector T cells. Recent findings on the mechanisms that underlie the increased frequency of severe pulmonary bacterial infections following respiratory virus infection are also discussed.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Innate immunity to respiratory virus infection.
Virus infection of respiratory epithelial cells is first detected by cytosolic and/or endosomal innate sensors in the infected epithelial cells (not shown). Recognition of the invading virus by these innate immune receptors leads to the production of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, and chemokines such as CC-chemokine ligand 2 (CCL2). These soluble mediators that are released by infected cells activate adjacent CD45− parenchymal cells, such as fibroblasts and epithelial cells, and neighbouring innate immune cells. Following activation, these cells convert latent transforming growth factor-β (TGFβ) to an active form, resulting in increased secretion of the chemokines CCL2 and CCL20 by parenchymal stromal cells and of cytokines such as IL-12 and tumour necrosis factor (TNF) by inflammatory cells. This enhanced production of chemokines and cytokines facilitates the maturation of tissue-resident CD103+ and CD11b+ dendritic cells (DCs) and the recruitment and maturation of monocyte-derived DCs. Antigen acquisition and activation of immature antigen-bearing respiratory DCs results in their mobilization and migration out of the infected lungs along chemokine gradients of CCL21 and sphingosine-1-phosphate (S1P) to the lymph nodes draining the infected lung. Once in the lymph nodes, these DCs participate in initiating adaptive immune responses to the respiratory virus (not shown).
Figure 2
Figure 2. Regulatory mechanisms in the lung during respiratory virus infection.
Molecules derived from both innate and adaptive immune cells contribute to the regulation of excessive pulmonary inflammation during acute respiratory virus infection. CD4+ T helper 1 (TH1) cells and type 1 CD8+ cytotoxic T cells (TC1 cells) express the transcription factors T-bet and BLIMP1 (B lymphocyte-induced maturation protein 1) and produce high levels of the regulatory cytokine interleukin-10 (IL-10), in addition to effector cytokines and cytolytic molecules, during respiratory virus infection. Regulatory T (TReg) cells in the lungs also express the 'effector' transcription factors T-bet and BLIMP1, produce various immunoregulatory cytokines (including IL-10 and transforming growth factor-β1 (TGFβ1)) and express the inhibitory receptor cytotoxic T-lymphocyte antigen 4 (CTLA4). Lung epithelial cells express CD200 and are required for the control of exuberant activation of classically activated macrophages. By contrast, alternatively activated macrophages contribute to the control of excessive pulmonary inflammation. Plasmacytoid dendritic cells (pDCs) also contribute to the suppression of excessive T cell-mediated inflammation through an unidentified mechanism. iNOS, inducible nitric oxide synthase; PPARγ, peroxisome proliferator-activated receptor-γ; TNF, tumour necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand.
Figure 3
Figure 3. Respiratory virus infection and susceptibility to secondary bacterial infection.
Multiple distinct mechanisms have been postulated to account for the increased susceptibility to bacterial superinfection and bacterial pneumonia following infection with respiratory viruses such as type A influenza viruses. Influenza virus infection induces the production of type I interferons (IFNs), which inhibit the recruitment of circulating neutrophils and macrophages to the lung following bacterial challenge. Type I IFNs also inhibit the differentiation of antibacterial T helper 17 (TH17) cells from naive T cells (TH0 cells) or other TH cell types (such as TH1 and TH2 cells) and thereby potentiate host susceptibility to secondary bacterial infection. IFNγ production by influenza virus-specific effector T cells decreases the expression of macrophage receptor with collagenous structure (MARCO) by alveolar macrophages and inhibits the ingestion of bacteria by these cells. Moreover, interleukin-10 (IL-10) production by influenza virus-specific effector T cells may inhibit the ability of innate immune cells, in particular macrophages, to kill bacteria. Finally, the direct interaction and/or infection of innate immune cells — such as macrophages, neutrophils and natural killer (NK) cells — with influenza virus suppresses the ability of these cells to take up and kill bacteria.
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