Tregs control the development of symptomatic West Nile virus infection in humans and mice
Marion C. Lanteri, … , Michael S. Diamond, Philip J. Norris
Marion C. Lanteri, … , Michael S. Diamond, Philip J. Norris
Published October 12, 2009
Citation Information: J Clin Invest. 2009;119(11):3266-3277. https://doi.org/10.1172/JCI39387.
View: Text | PDF
Research Article Infectious disease

Tregs control the development of symptomatic West Nile virus infection in humans and mice

Abstract

West Nile virus (WNV) causes asymptomatic infection in most humans, but for undefined reasons, approximately 20% of immunocompetent individuals develop West Nile fever, a potentially debilitating febrile illness, and approximately 1% develop neuroinvasive disease syndromes. Notably, since its emergence in 1999, WNV has become the leading cause of epidemic viral encephalitis in North America. We hypothesized that CD4+ Tregs might be differentially regulated in subjects with symptomatic compared with those with asymptomatic WNV infection. Here, we show that in 32 blood donors with acute WNV infection, Tregs expanded significantly in the 3 months after index (RNA+) donations in all subjects. Symptomatic donors exhibited lower Treg frequencies from 2 weeks through 1 year after index donation yet did not show differences in systemic T cell or generalized inflammatory responses. In parallel prospective experimental studies, symptomatic WNV-infected mice also developed lower Treg frequencies compared with asymptomatic mice at 2 weeks after infection. Moreover, Treg-deficient mice developed lethal WNV infection at a higher rate than controls. Together, these results suggest that higher levels of peripheral Tregs after infection protect against severe WNV disease in immunocompetent animals and humans.

Authors

Marion C. Lanteri, Katie M. O’Brien, Whitney E. Purtha, Mark J. Cameron, Jennifer M. Lund, Rachel E. Owen, John W. Heitman, Brian Custer, Dale F. Hirschkorn, Leslie H. Tobler, Nancy Kiely, Harry E. Prince, Lishomwa C. Ndhlovu, Douglas F. Nixon, Hany T. Kamel, David J. Kelvin, Michael P. Busch, Alexander Y. Rudensky, Michael S. Diamond, Philip J. Norris

×

Figure 1

Identification of Tregs.

Options: View larger image (or click on image) Download as PowerPoint
Identification of Tregs. PBMCs were stained ex vivo for CD3, CD4, CD25, ...
PBMCs were stained ex vivo for CD3, CD4, CD25, Foxp3, CD152, and CD127. Lymphocytes were gated and dead cells excluded. (A) The Foxp3 cell gate was set to exclude Foxp3– and CD25– events within CD3+CD4+ cell populations. CD152+CD127– events were measured in CD25+Foxp3+lo (52%) and CD25+Foxp3+hi cells (95%) and in (B) CD25neg (4%), CD25int (5%), and CD25hi cells (63%). Levels of CD152, CD127, and Foxp3 staining were measured in CD25neg, CD25int, and CD25hi populations using selected gates. (C) CD25hi cells were 68.9% CD152+, 14.3% CD127–, and 80.7% Foxp3+, compared with respective values of 13.2%, 89.9%, and 3.7% for CD25int cells and 8.6%, 79.8%, and 0.6% for CD25neg cells. Results are from 1 representative of 3 normal human controls tested in 4 independent experiments. (D) Agarose gel with DNA stained with ethidium bromide. Expression of Foxp3 in CD4+CD25+ T cells compared with PBMCs or CD4+CD25– T cells, normalized for RNA input using β-actin primers (gel representative of 3 different experiments).