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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0804119v1 183/5/3472    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Venet, F. Articles by Ayala, A. PubMed PubMed Citation Articles by Venet, F. Articles by Ayala, A.

Lymphocytes in the Development of Lung Inflammation: A Role for Regulatory CD4⁺ T Cells in Indirect Pulmonary Lung Injury¹

Division of Surgical Research, Rhode Island Hospital, Providence, RI 02903

Although roles for myelocytes have been suggested in the pathophysiology of indirect acute lung injury (ALI not due to a direct insult to the lung), the contribution of various regulatory lymphoid subsets is unknown. We hypothesized a role for lymphocytes in this process. Using a sequential model of indirect ALI induced in mice by hemorrhagic shock followed 24 h later by polymicrobial sepsis; we observed a specific and nonredundant role for each lymphocyte subpopulation in indirect ALI pathophysiology. In particular, we showed that CD4⁺ T cells are specifically recruited to the lung in a dendritic cell-independent but IL-16-dependent process and diminish neutrophil recruitment through increased IL-10 production. Most importantly, this appears to be mediated by the specific subpopulation of CD4⁺CD25⁺Foxp3⁺ regulatory T cells. Although indirect ALI has constantly been described as a proinflammatory pathology mediated by cells of the innate immune system, we now demonstrate that cells of the adaptive immune response play a major role in its pathophysiology as well. Most importantly, we also describe for the first time the nature of the regulatory mechanisms activated in the lung during indirect ALI, with CD4⁺ regulatory T cells being central to the control of neutrophil recruitment via increased IL-10 production.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01 HL73525 (to A.A.). Purchase and operation of FACSAria were supported by National Center for Research Resources-Shared Instruments Grant 1S10RR021051-01A2.

² Address correspondence and reprint requests to Dr. Alfred Ayala, Division of Surgical Research, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903. E-mail address: AAyala{at}Lifespan.org

³ Abbreviations used in this paper: ALI, acute lung injury; ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease; Hem, hemorrhagic shock; CLP, cecal ligation and puncture; BALF, bronchoalveolar lavage fluid; siRNA, small interfering RNA; IT, intratracheal(ly); DOTAP, N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulfate; DC, dendritic cell; MHC II, MHC class II; KC, keratinocyte-derived chemokine; Treg, regulatory T cell; EGFP, enhanced GFP; MPO, myeloperoxidase; DTR, diphtheria toxin receptor.