Coordination of Early Protective Immunity to Viral Infection by Regulatory T Cells

Jennifer M. Lund, Lianne Hsing, Thuy T. Pham, Alexander Y. Rudensky^*

Abstract: Suppression of immune responses by regulatory T cells (Tregs) is thought to limit late stages of pathogen-specific immunity as a means of minimizing associated tissue damage. We examined a role for Tregs during mucosal herpes simplex virus infection in mice, and observed an accelerated fatal infection with increased viral loads in the mucosa and central nervous system after ablation of Tregs. Although augmented interferon production was detected in the draining lymph nodes (dLNs) in Treg-deprived mice, it was profoundly reduced at the infection site. This was associated with a delay in the arrival of natural killer cells, dendritic cells, and T cells to the site of infection and a sharp increase in proinflammatory chemokine levels in the dLNs. Our results suggest that Tregs facilitate early protective responses to local viral infection by allowing a timely entry of immune cells into infected tissue.

Department of Immunology and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.

^* To whom correspondence should be addressed. E-mail: aruden{at}u.washington.edu

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J. Virol. 87, 6161-6171
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 |  Abstract »  |  Full Text »  |  PDF »

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 |  Abstract »  |  Full Text »  |  PDF »

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J. Immunol. 189, 5924-5933
 |  Abstract »  |  Full Text »  |  PDF »

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 |  Abstract »  |  Full Text »  |  PDF »

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 |  Abstract »  |  Full Text »  |  PDF »

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 |  Abstract »  |  Full Text »  |  PDF »

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C. Y. Chen, D. Huang, S. Yao, L. Halliday, G. Zeng, R. C. Wang, and Z. W. Chen (2012)
J. Immunol. 188, 4278-4288
 |  Abstract »  |  Full Text »  |  PDF »

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J. Immunol. 188, 3678-3685
 |  Abstract »  |  Full Text »  |  PDF »

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 |  Abstract »  |  Full Text »  |  PDF »

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R. J. Betts, N. Prabhu, A. W. S. Ho, F. C. Lew, P. E. Hutchinson, O. Rotzschke, P. A. Macary, and D. M. Kemeny (2012)
J. Virol. 86, 2817-2825
 |  Abstract »  |  Full Text »  |  PDF »

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A. Benson, S. Murray, P. Divakar, N. Burnaevskiy, R. Pifer, J. Forman, and F. Yarovinsky (2012)
J. Immunol. 188, 800-810
 |  Abstract »  |  Full Text »  |  PDF »

Tregs and infections: on the potential value of modifying their function.

S. Sehrawat and B. T. Rouse (2011)
J. Leukoc. Biol. 90, 1079-1087
 |  Abstract »  |  Full Text »  |  PDF »

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B. Baban, P. R. Chandler, B. A. Johnson III, L. Huang, M. Li, M. L. Sharpe, L. M. Francisco, A. H. Sharpe, B. R. Blazar, D. H. Munn, et al. (2011)
J. Immunol. 187, 2329-2335
 |  Abstract »  |  Full Text »  |  PDF »

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T.-L. M. Nguyen, N. L. Sullivan, M. Ebel, R. M. Teague, and R. J. DiPaolo (2011)
J. Immunol. 187, 1745-1753
 |  Abstract »  |  Full Text »  |  PDF »

IFN-{gamma}- and IL-10-expressing virus epitope-specific Foxp3+ T reg cells in the central nervous system during encephalomyelitis.

J. Zhao, J. Zhao, C. Fett, K. Trandem, E. Fleming, and S. Perlman (2011)
J. Exp. Med. 208, 1571-1577
 |  Abstract »  |  Full Text »  |  PDF »

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Blood 117, 5372-5380
 |  Abstract »  |  Full Text »  |  PDF »

Physiologic Control of the Functional Status of Foxp3+ Regulatory T Cells.

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J. Immunol. 186, 4535-4540
 |  Abstract »  |  Full Text »  |  PDF »

Serum amyloid A overrides Treg anergy via monocyte-dependent and Treg-intrinsic, SOCS3-associated pathways.

K. D. Nguyen, C. Macaubas, K. C. Nadeau, P. Truong, T. Yoon, T. Lee, J. L. Park, and E. D. Mellins (2011)
Blood 117, 3793-3798
 |  Abstract »  |  Full Text »  |  PDF »

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 |  Full Text »  |  PDF »

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PNAS 108, 4623-4630
 |  Abstract »  |  Full Text »  |  PDF »

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U. Schenk, M. Frascoli, M. Proietti, R. Geffers, E. Traggiai, J. Buer, C. Ricordi, A. M. Westendorf, and F. Grassi (2011)
Science Signaling 4, ra12
 |  Abstract »  |  Full Text »  |  PDF »

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G. A. Punkosdy, M. Blain, D. D. Glass, M. M. Lozano, L. O'Mara, J. P. Dudley, R. Ahmed, and E. M. Shevach (2011)
PNAS 108, 3677-3682
 |  Abstract »  |  Full Text »  |  PDF »

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J. Virol. 85, 1625-1633
 |  Abstract »  |  Full Text »  |  PDF »

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J. Virol. 85, 1287-1297
 |  Abstract »  |  Full Text »  |  PDF »

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 |  Abstract »  |  Full Text »  |  PDF »

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 |  Abstract »  |  Full Text »  |  PDF »

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J. Immunol. 185, 5983-5992
 |  Abstract »  |  Full Text »  |  PDF »

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L. E. Yauch, T. R. Prestwood, M. M. May, M. M. Morar, R. M. Zellweger, B. Peters, A. Sette, and S. Shresta (2010)
J. Immunol. 185, 5405-5416
 |  Abstract »  |  Full Text »  |  PDF »

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J. Exp. Med. 207, 2323-2330
 |  Abstract »  |  Full Text »  |  PDF »

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J. Liu, T. J. Ruckwardt, M. Chen, J. D. Nicewonger, T. R. Johnson, and B. S. Graham (2010)
J. Virol. 84, 10501-10509
 |  Abstract »  |  Full Text »  |  PDF »

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J. Virol. 84, 8790-8798
 |  Abstract »  |  Full Text »  |  PDF »

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R. B. Fulton, D. K. Meyerholz, and S. M. Varga (2010)
J. Immunol. 185, 2382-2392
 |  Abstract »  |  Full Text »  |  PDF »

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J. Immunol. 185, 1351
 |  Full Text »  |  PDF »

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J. Immunol. 185, 1804-1811
 |  Abstract »  |  Full Text »  |  PDF »

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E.-J. Freyschmidt, C. B. Mathias, N. Diaz, D. H. MacArthur, A. Laouar, N. Manjunath, M. D. Hofer, M.-A. Wurbel, J. J. Campbell, T. A. Chatila, et al. (2010)
J. Immunol. 185, 1295-1302
 |  Abstract »  |  Full Text »  |  PDF »

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J. Immunol. 185, 1132-1141
 |  Abstract »  |  Full Text »  |  PDF »

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S. Shafiani, G. Tucker-Heard, A. Kariyone, K. Takatsu, and K. B. Urdahl (2010)
J. Exp. Med. 207, 1409-1420
 |  Abstract »  |  Full Text »  |  PDF »

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C. J. Winstead, C. S. Reilly, J. J. Moon, M. K. Jenkins, S. E. Hamilton, S. C. Jameson, S. S. Way, and A. Khoruts (2010)
J. Immunol. 184, 4749-4760
 |  Abstract »  |  Full Text »  |  PDF »

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J. Immunol. 184, 4391-4400
 |  Abstract »  |  Full Text »  |  PDF »

Transient role of CD4+CD25+ regulatory T cells in mycobacterial infection in mice.

Y. Ozeki, I. Sugawara, T. Udagawa, T. Aoki, M. Osada-Oka, Y. Tateishi, H. Hisaeda, Y. Nishiuchi, N. Harada, K. Kobayashi, et al. (2010)
Int. Immunol. 22, 179-189
 |  Abstract »  |  Full Text »  |  PDF »

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S. R. Nair, G. Zelinskyy, S. Schimmer, N. Gerlach, G. Kassiotis, and U. Dittmer (2010)
J. Gen. Virol. 91, 440-451
 |  Abstract »  |  Full Text »  |  PDF »

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B. P. Doehle, F. Hladik, J. P. McNevin, M. J. McElrath, and M. Gale Jr. (2009)
J. Virol. 83, 10395-10405
 |  Abstract »  |  Full Text »  |  PDF »

The regulatory T-cell response during acute retroviral infection is locally defined and controls the magnitude and duration of the virus-specific cytotoxic T-cell response.

G. Zelinskyy, K. K. Dietze, Y. P. Husecken, S. Schimmer, S. Nair, T. Werner, K. Gibbert, O. Kershaw, A. D. Gruber, T. Sparwasser, et al. (2009)
Blood 114, 3199-3207
 |  Abstract »  |  Full Text »  |  PDF »

How Diverse--CD4 Effector T Cells and their Functions.

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J Mol Cell Biol 1, 20-36
 |  Abstract »  |  Full Text »  |  PDF »

CD4+ CD25+ Foxp3- T-Regulatory Cells Produce both Gamma Interferon and Interleukin-10 during Acute Severe Murine Spotted Fever Rickettsiosis.

R. Fang, N. Ismail, T. Shelite, and D. H. Walker (2009)
Infect. Immun. 77, 3838-3849
 |  Abstract »  |  Full Text »  |  PDF »

Superantigen-Activated Regulatory T Cells Inhibit the Migration of Innate Immune Cells and the Differentiation of Naive T Cells.

Y. Tanriver, A. Martin-Fontecha, K. Ratnasothy, G. Lombardi, and R. Lechler (2009)
J. Immunol. 183, 2946-2956
 |  Abstract »  |  Full Text »  |  PDF »

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W. E. O'Gorman, H. Dooms, S. H. Thorne, W. F. Kuswanto, E. F. Simonds, P. O. Krutzik, G. P. Nolan, and A. K. Abbas (2009)
J. Immunol. 183, 332-339
 |  Abstract »  |  Full Text »  |  PDF »

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J. Immunol. 182, 7490-7500
 |  Abstract »  |  Full Text »  |  PDF »

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J. Virol. 83, 3019-3028
 |  Abstract »  |  Full Text »  |  PDF »

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K. N. Couper, P. A. Lanthier, G. Perona-Wright, L. W. Kummer, W. Chen, S. T. Smiley, M. Mohrs, and L. L. Johnson (2009)
J. Immunol. 182, 3985-3994
 |  Abstract »  |  Full Text »  |  PDF »

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 |  Abstract »  |  Full Text »  |  PDF »

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 |  Abstract »  |  Full Text »  |  PDF »