TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection

Abstract

Respiratory infection with highly pathogenic influenza A viruses is characterized by the exuberant production of cytokines and chemokines and the enhanced recruitment of innate inflammatory cells. Here, we show that challenging mice with virulent influenza A viruses, including currently circulating H5N1 strains, causes the increased selective accumulation of a particular dendritic cell subset, the tipDCs, in the pneumonic airways. These tipDCs are required for the further proliferation of influenza-specific CD8 ؉ T cells in the infected lung, because blocking their recruitment in CCR2 ؊/؊ mice decreases the numbers of CD8 ؉ effectors and ultimately compromises virus clearance. However, diminution rather than total elimination of tipDC trafficking by treatment with the peroxisome proliferator-activated receptor-␥ agonist pioglitazone moderates the potentially lethal consequences of excessive tipDC recruitment without abrogating CD8 ؉ T cell expansion or compromising virus control. Targeting the tipDCs in this way thus offers possibilities for therapeutic intervention in the face of a catastrophic pandemic.H5N1 ͉ inflammation ͉ pathogenesis

Human CD8+ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

“…Since they also expressed CD83 (Fig. 3C), TNF-a and iNOS, they could resemble Tip-DCs previously described in mice [3][4][5] and humans [22]. …”

“…While DCs display a dendritic form and exhibit DC functions during steady state, inflammatory DCs, derived from CCR2 1 monocytes, only appear as a consequence of infection or inflammation [2]. Recent studies in mice have identified a subset of inflammatory DCs, known as TNF/iNOS-producing DCs (Tip-DCs), that are important for the clearance of Listeria monocytogenes bacteria [3]; influenza virus [4]; and regulation of IgA production in mucosal immunity [5]. Since the differentiation of monocytes into DCs or macrophages relies on the microenvironment, the presence of different T-cell types and cytokines is a critical feature in determining the differentiation outcome [6].…”

“…CD8 1 T cells utilize a variety of factors, including IFN-g, GM-CSF, TNF-a and CD40L to activate DCs for the production of 13,14], the key cytokine for Th1 immunity [15]. Importantly, CD8 1 T cells were shown to interact with DCs in both lymph nodes [16] and peripheral tissue sites [4,17] where they exert their pro-Th1 influence.Previous studies have shown that CD8 1 T cells are able to infiltrate quickly into inflamed sites [18] that may facilitate their early interaction with DCs. In human psoriasis studies, the administration of alefacept, which reduces infiltration of activated memory CD8 1 T cells, reduced DC content, inflammation and tissue expression of iNOS and .…”

The therapeutic effects of sodium cromoglycate against influenza A virus H5N1 in mice

“…However, the overexpression of these cytokines causes a variety of complications and pathological injuries. Previous studies reported that TNF‐α and IL‐6 could aggravate the clinical symptoms and histopathological changes of influenza virus‐infected mice 41, 42. We hypothesize that SCG could stabilize the membrane of mast cells, which inhibits the release of inflammatory mediators and alleviates the inflammatory response induced by H5N1 infection.…”

Functional regulation of monocyte-derived dendritic cells by microRNAs

“…Functionally, moDCs are major producers of pro-inflammatory cytokines (Serbina et al, 2003;Xu et al, 2007;Zhan et al, 2010), inducers of Th1 differentiation (Leon et al, 2007) and memory T cell activation (Wakim et al, 2008), and antigen cross-presenting cells (Cheong et al, 2010). By exhibiting these potent functions, moDCs offer a protective immunity role as well as mediate immunopathology (Aldridge et al, 2009). In autoimmune inflammation, moDCs are likely to be the major mediators of pathology (Campbell et al, 2011).…”