Control of Borrelia burgdorferi-specific CD4+-T-cell effector function by interleukin-12- and T-cell receptor-induced p38 mitogen-activated protein kinase activity.
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.
Hedrick
Michael N
MN
Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina 28223, USA.
Olson
Chris M
CM
Conze
Dietrich B
DB
Bates
Tonya C
TC
Rincón
Mercedes
M
Anguita
Juan
J
D000818:Animals; D025065:Borrelia burgdorferi; D015704:CD4 Antigens / Q000032:analysis; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000097:blood; D018664:Interleukin-12 / Q000502:physiology*; D008193:Lyme Disease / Q000201:enzymology / Q000276:immunology*; D048371:MAP Kinase Kinase 3 / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D015704:CD4 Antigens; D047428:Protein Kinase Inhibitors; D011948:Receptors, Antigen, T-Cell; D018664:Interleukin-12; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3