Control of Borrelia burgdorferi-specific CD4+-T-cell effector function by interleukin-12- and T-cell receptor-induced p38 mitogen-activated protein kinase activity

Infect Immun. 2006 Oct;74(10):5713-7. doi: 10.1128/IAI.00623-06.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Borrelia burgdorferi*
  • CD4 Antigens / analysis
  • Female
  • Interferon-gamma / biosynthesis*
  • Interferon-gamma / blood
  • Interleukin-12 / physiology*
  • Lyme Disease / enzymology
  • Lyme Disease / immunology*
  • MAP Kinase Kinase 3 / genetics
  • Mice
  • Mice, Inbred Strains
  • Mutation
  • Protein Kinase Inhibitors / pharmacology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • Th1 Cells / drug effects
  • Th1 Cells / enzymology
  • Th1 Cells / immunology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • CD4 Antigens
  • Protein Kinase Inhibitors
  • Receptors, Antigen, T-Cell
  • Interleukin-12
  • Interferon-gamma
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 3