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Blood, 15 April 2008, Vol. 111, No. 8, pp. 4184-4192.
Prepublished online as a Blood First Edition Paper on January 24, 2008; DOI 10.1182/blood-2007-08-108936.
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Submitted August 24, 2007
Accepted January 6, 2008
Novel biphasic role for lymphocytes revealed during resolving inflammation
Ravindra Rajakariar, Toby Lawrence, Jonas Bystrom, Mark Hilliard, Paul Colville-Nash, Geoff Bellingan, Desmond Fitzgerald, Muhammad M. Yaqoob, and Derek W. Gilroy*
Department of Experimental Medicine and Translational Therapeutics, William Harvey Research Institute, London, United Kingdom
Institute of Cancer, Centre for Translational Oncology, London, United Kingdom
Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, United Kingdom
Conway Institute, University College Dublin, Dublin, Republic of Ireland
SW Thames Institute for Renal Research, St. Helier Hospital, Surrey, United Kingdom
Critical Care, University College London Hospitals NHS Foundation Trust, London, United Kingdom
* Corresponding author; email: d.gilroy{at}ucl.ac.uk.
Acute inflammation is traditionally described as the influx of PMNs followed by monocyte-derived macrophages leading to resolution. This is a classic view and despite sub-populations of lymphocytes possessing innate immune-regulatory properties, seldom is their role in acute inflammation and its resolution discussed. To redress this we show, using lymphocyte-deficient RAG1-/- mice, that peritoneal T/B lymphocytes control PMN trafficking by regulating cytokine synthesis. Once inflammation ensues in normal mice, lymphocytes disappear in response to DP1 receptor activation by prostaglandin D2. However, upon resolution lymphocytes repopulate the cavity comprising B1, NK, gamma/delta T, CD4+/CD25+ and B2 cells. Repopulating lymphocytes are dispensable for resolution as inflammation in RAG1-/- and wild-types resolves uniformly. However, repopulating lymphocytes are critical for modulating responses to superinfection. Thus, in chronic granulomatous disease using gp91phox-/- mice not only is resolution delayed compared to wild types but there is a failure of lymphocyte reappearance predisposing to exaggerated immune responses upon secondary challenge that is rescued by resolution-phase lymphocytes. In conclusion, as lymphocyte repopulation is also evident in human peritonitis, we hereby describe a transition in T/B cells from acute inflammation to resolution with a central role in modulating the severity of early onset and orchestrating responses to secondary infection.
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