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Role of regulatory T cells in long-term immune dysfunction associated with severe sepsis

Nascimento, Daniele C. MsC; Alves-Filho, José C. PhD; Sônego, Fabiane MsC; Fukada, Sandra Y. PhD; Pereira, Marcelo S. MsC; Benjamim, Claudia PhD; Zamboni, Dario S. PhD; Silva, João S. PhD; Cunha, Fernando Q. PhD

doi: 10.1097/CCM.0b013e3181e78ad0
Laboratory Investigations

Objective: To investigate the role of regulatory T cells in the modulation of long-term immune dysfunction during experimental sepsis. It is well established that sepsis predisposes to development of a pronounced immunosuppression. Nevertheless, the mechanisms underlying the immune dysfunction after sepsis are still not well understood.

Design: Prospective experimental study.

Setting: University research laboratory.

Interventions: Wild-type mice underwent cecal ligation and puncture and were treated with antibiotic during 3 days after surgery. On days 1, 7, or 15 after cecal ligation and puncture, the frequency of regulatory T cells, proliferation of CD4+ T cells and bacterial counts were evaluated. Fifteen days after cecal ligation and puncture, surviving mice underwent secondary pulmonary infection by intranasal inoculation of nonlethal dose of Legionella pneumophila. Some mice received agonistic glucocorticoid-induced tumor necrosis factor receptor antibody (DTA-1) before induction of secondary infection.

Measurements and Main Results: Mice surviving cecal ligation and puncture showed a markedly increased frequency of regulatory T cells in thymus and spleen, which was associated with reduced proliferation of CD4+ T cells. Fifteen days after cecal ligation and puncture, all sepsis-surviving mice succumbed to nonlethal injection of L. pneumophila. Treatment of mice with DTA-1 antibody reduced frequency of regulatory T cells, restored CD4+ T cell proliferation, reduced the levels of bacteria in spleen, and markedly improved survival of L. pneumophila infection.

Conclusion: These findings suggest that regulatory T cells play an important role in the progression and establishment of immune dysfunction observed in experimental sepsis.

From the Departments of Biochemistry and Immunology (DCN, JSS, FQC), Pharmacology (JCA-F, FS, SYF), and Cell Biology and Microbial Pathogenesis (MSP, DSZ), School of Medicine at Ribeirao Preto, University of São Paulo, Ribeirao Preto, São Paulo, Brazil; Cellular and Molecular Pharmacology Program (CFB), Institute of Biomedical Science, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Drs. Nascimento and Alves-Filho contributed equally to this work.

This study was supported, in part, by grants from the Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico (CNPq) (FDQ, JSS), Fundacão de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (FDQ, JSS, DSZ), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ccmjournal.com). Figure legends for Supplemental Figures 1–3 are available at http://links.lww.com/CCM/A148.

The authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: fdqcunha@fmrp.usp.br

© 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins