Pivotal Advance: Invariant NKT cells reduce accumulation of inflammatory monocytes in the lungs and decrease immune-pathology during severe influenza

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Published online before print October 14, 2011, doi: 10.1189/jlb.0411184 March 2012 Journal of Leukocyte Biology vol. 91 no. 3 357-368


Pivotal Advance: Invariant NKT cells reduce accumulation of inflammatory monocytes in the lungs and decrease immune-pathology during severe influenza A virus infection

Wai Ling Kok*,
Laura Denney*,
Kambez Benam*,
Suzanne Cole*,
Colin Clelland?,
Andrew J. McMichael* and
Ling-Pei Ho*,?,1

+ Author Affiliations

*MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom;
?Pathology Department, The John Radcliffe Hospital, Oxford, United Kingdom; and
?Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford, United Kingdom

↵1.Correspondence: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, UK. E-mail: ling-pei.ho@imm.ox.ac.uk

Abstract

Little is known of how a strong immune response in the lungs is regulated to minimize tissue injury during severe influenza A virus (IAV) infection. Here, using a model of lethal, high-pathogenicity IAV infection, we first show that Ly6ChiLy6G? inflammatory monocytes, and not neutrophils, are the main infiltrate in lungs of WT mice. Mice devoid of iNKT cells (Jα18−/− mice) have increased levels of inflammatory monocytes, which correlated with increased lung injury and mortality (but not viral load). Activation of iNKT cells correlated with reduction of MCP-1 levels and improved outcome. iNKT cells were able to selectively lyse infected, MCP-1-producing monocytes in vitro, in a CD1d-dependent process. Our study provides a detailed profile and kinetics of innate immune cells in the lungs during severe IAV infection, highlighting inflammatory monocytes as the major infiltrate and identifying a role for iNKT cells in control of these cells and lung immune-pathology.


http://www.jleukbio.org/content/91/3/357

 

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Re: Pivotal Advance: Invariant NKT cells reduce accumulation of inflammatory monocytes in the lungs and decrease immune-pathology during severe influenza A virus infection

Editorial: NKT get the 'flu: NKT cells as (mostly) good guys in influenza; monocytic cells as double agents

Mark A. Exley1

+ Author Affiliations

Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

↵1.Correspondence: Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave., RW 633, Harvard Medical School, Boston, MA 02215, USA. E-mail: mexley@bidmc.harvard.edu

α-galactosylceramide
virus
CD1d
iNKT

A CD1d-restricted subset of NKT includes conserved immune elements with positive and negative regulatory activity in immunity, including pathogen resistance. NKT cells have been shown to have physiological, protective effects in certain but not all virus infections via contributing to activation of first NK cells and subsequently, T and B cells. NKT cells can also promote the switch to a regulatory environment, limiting successful as well as pathologic adaptive responses. However, as with any immune element, excessive or chronic NKT proinflammatory activities can lead to tissue injury, for example, in myocarditis, lung diseases, and hepatitis, as a result of viral infections. The NKT role in influenza infection is only recently becoming clear. Although in certain pulmonary infections, NKT cells can promote damaging inflammation, several recent studies, including one in this issue of the Journal of Leukocyte Biology [1], find that NKT can limit excessive lung inflammation by monocytic-type myeloid cells.
CONTRASTING ROLES OF NKT CELLS IN IMMUNOSURVEILLANCE VERSUS IMMUNOPATHOLOGY WITH DISTINCT VIRUSES

NKT populations have significant positive or negative roles in regulating immunity, including surveillance against certain pathogens [2, 3]. The major functionally defined, CD1d-restricted subset of NKT includes innate-type T cells, recognizing exogenous and partially defined endogenous lipid antigens presented by monomorphic MHC-like CD1d. There are two main sources of CD1d reactivity: the best-known iTCR-α, expressing a ?Type 1? subset of NKT (iNKT) and ?Type 2? (polyclonal/noninvariant) [2, 3]. iNKT make up only a small fraction of human CD1d-reactive NKT and are the minority in rodent spleen and bone marrow [2, 3]. Exogenous CD1d ligands include prototypic, high-affinity iNKT-specific αGC [2, 3]. CD1d is expressed by DCs and other APCs, as well as in certain tissues, and can be increased under inflammatory conditions, including potentially, in influenza [4].

The NKT:CD1d system is a potent and ?


http://www.jleukbio.org/content/91/3/349

 

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Re: Pivotal Advance: Invariant NKT cells reduce accumulation of inflammatory monocytes in the lungs and decrease immune-pathology during severe influenza A virus infection

Discovery could prevent deaths from severe flu outbreaks

Researchers have stumbled on a new discovery that may help prevent deaths from severe flu outbreaks and also lung injuries, especially among seemingly healthy people.

Specifically, the researchers found that immune cells called "natural killer T cells" may reduce the overwhelming numbers of another type of immune cells called "inflammatory monocytes", which when present in large numbers lead to lung injury at the end stage of severe flu infection.

"We hope this study will ultimately benefit individuals, especially the young, who succumb to a severe form of flu infection," said Ling-Pei Ho, who led the work at the MRC Human Immunology Unit, Oxford University.

"The study highlights a key immune process that occurs in severe flu infection, and provides a platform for a new approach and further research in this area," added Ho, the Journal of Leukocyte Biology reports.

..


http://story.irishsun.com/index.php/ct/9/cid/2411cd3571b4f088/id/203904407/cs/1/