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Infection and Immunity, October 2006, p. 5713-5717, Vol. 74, No. 10
0019-9567/06/$08.00+0     doi:10.1128/IAI.00623-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Control of Borrelia burgdorferi-Specific CD4+-T-Cell Effector Function by Interleukin-12- and T-Cell Receptor-Induced p38 Mitogen-Activated Protein Kinase Activity

Michael N. Hedrick,1 Chris M. Olson Jr.,2 Dietrich B. Conze,3,{dagger} Tonya C. Bates,1,2 Mercedes Rincón,3 and Juan Anguita1,2*

Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina 28223,1 Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003,2 Immunobiology Program, Department of Internal Medicine, University of Vermont College of Medicine, Burlington, Vermont 054053

Received 18 April 2006/ Returned for modification 26 May 2006/ Accepted 6 July 2006

Infection with Borrelia burgdorferi, the causative agent of Lyme disease, results in a Th1 response and proinflammatory cytokine production. Mice deficient for MKK3, an upstream activator of p38 mitogen-activated protein (MAP) kinase, develop a lower Th1 response and exhibit an impaired ability to produce proinflammatory cytokines upon infection with the spirochete. We investigated the contribution of p38 MAP kinase activity in gamma interferon (IFN-{gamma}) production in CD4+ T cells in response to specific antigen through T-cell receptor (TCR)- and interleukin-12 (IL-12)-mediated signals. The specific inhibition of p38 MAP kinase in T cells and the administration of a pharmacological inhibitor of the kinase during the course of infection with the spirochete resulted in reduced levels of IFN-{gamma} in the sera of infected mice. Our results also demonstrate that although p38 MAP kinase activity is not required for the differentiation of B. burgdorferi-specific CD4+ T cells, the production of IFN-{gamma} by Th1 effector cells is regulated by the kinase. Both TCR engagement and IL-12 induced the production of the Th1 cytokine through the activation of the p38 MAP kinase pathway. Thus, the inhibition of this pathway in vitro resulted in decreased levels of IFN-{gamma} during restimulation of B. burgdorferi-specific T cells in response to anti-CD3 and IL-12 stimulation. These results clarify the specific contribution of the p38 MAP kinase in the overall immune response to the spirochete and its role in the effector function of B. burgdorferi-specific T cells.

* Corresponding author. Mailing address: Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, 103 Paige Lab, 161 Holdsworth Way, Amherst, MA 01003. Phone: (413) 577-3317. Fax: (413) 545-6326. E-mail: janguita{at}vasci.umass.edu.

Editor: D. L. Burns

{dagger} Present address: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

Infection and Immunity, October 2006, p. 5713-5717, Vol. 74, No. 10
0019-9567/06/$08.00+0     doi:10.1128/IAI.00623-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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