Increased circulating regulatory T cells (CD4+CD25+CD127−) contribute to lymphocyte anergy in septic shock patients
- 570 Downloads
Sepsis syndrome represents the leading cause of death in intensive care unit. Patients present features consistent with a decline in immune responsiveness potentially contributing to mortality. We investigated whether CD4+CD25+ regulatory T cells (Treg) participate in the induction of lymphocyte anergy after sepsis.
Observational study in septic shock patients and experimental study in mice.
We took advantage of the recently described flow cytometric gating strategy using the measurement of CD25 and CD127 expressions for monitoring Treg (CD4+CD25+CD127−Foxp3+). In patients the increased circulating Treg percentage significantly correlated with a decreased lympho-proliferative response. In a murine model of sepsis mimicking these observations, the ex vivo downregulation of Foxp3 expression using siRNA was associated with a restoration of this response.
The relative increase in circulating Treg might play a role in lymphocyte anergy described after septic shock and represent a standardizable surrogate marker of declining proliferative capacity after sepsis.
KeywordsSeptic shock Anergy CD4+CD25+ CD127 Regulatory T cells Foxp3
Aspects of the work presented here were supported by funds from the Hospices Civils de Lyon (to G.M.) and a grant from the NIH R01 GM46354 (to A.A.). The study was conducted thanks to the logistic support of Centre d’Investigation Clinique (CIC 201) of INSERM and Hospices Civils de Lyon. None of the authors has any potential financial conflict of interest related to this manuscript.
- 9.Roth G, Moser B, Krenn C, Brunner M, Haisjackl M, Almer G, Gerlitz S, Wolner E, Boltz-Nitulescu G, Ankersmit HJ (2003) Susceptibility to programmed cell death in T-lymphocytes of septic patients: a mechanism of lymphopenia and Th2 predominance. Biochem Biophys Res Comm 308:840–846PubMedCrossRefGoogle Scholar
- 15.Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, Solomon M, Selby W, Alexander SI, Nanan R, Kelleher A, Fazekas de St Groth B (2006) Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 203:1693–1700PubMedCrossRefGoogle Scholar
- 16.Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, Clayberger C, Soper DM, Ziegler SF, Bluestone JA (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203:1701–1711PubMedCrossRefGoogle Scholar
- 17.Venet F, Chung CS, Lepape A, Ayala A, Monneret G (2008) Anergy in septic patients: correlating the increased percentage of circulating CD4+CD25+CD127− regulatory T cells with a decline in lymphocyte proliferation. FASEB J 22:848–849Google Scholar
- 29.Scumpia PO, Delano MJ, Kelly KM, O’Malley KA, Efron PA, McAuliffe PF, Brusko T, Ungaro R, Barker T, Wynn JL, Atkinson MA, Reeves WH, Salzler MJ, Moldawer LL (2006) Increased natural CD4+CD25+ regulatory T cells and their suppressor activity do not contribute to mortality in murine polymicrobial sepsis. J Immunol 177:7943–7949PubMedGoogle Scholar
- 40.Hubbard WJ, Choudhry M, Schwacha MG, Kerby JD, Rue LW 3rd, Bland KI, Chaudry IH (2005) Cecal ligation and puncture. Shock 24S1:52–57Google Scholar
- 45.Codarri L, Vallotton L, Ciuffreda D, Venetz JP, Garcia M, Hadaya K, Buhler L, Rotman S, Pascual M, Pantaleo G (2007) Expansion and tissue infiltration of an allospecific CD4+CD25+CD45RO+IL-7Ralphahigh cell population in solid organ transplant recipients. J Exp Med 207:1533–1541CrossRefGoogle Scholar