Sequential production of Th1 and Th2 cytokines in response to live bacillus Calmette-Guérin.
Causes of individual variation in susceptibility to mycobacterial diseases are only partly understood. An efficient cell-mediated immune response is crucial for resistance. Macrophages and T cells interact to eliminate the mycobacteria, partially through the effects of secreted cytokines. A vigorous anti-bacterial inflammatory response is sometimes accompanied by severe tissue damage, while immunosuppression leads to progressive infection. Here, live, attenuated Mycobacterium bovis, bacillus Calmette-Guérin (BCG), was used as a model antigen to study cytokine production at the single-cell level in response to mycobacteria. Peripheral blood mononuclear cells from healthy individuals were challenged in vitro and the kinetics and frequencies of cytokine-producing cells were studied by immunofluorescent visualization of intracellular cytokines. Fourteen cytokines were assayed; interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-1 receptor antagonist (IL-1ra), IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), TNF-beta and granulocyte-macrophage colony-stimulating factor (GM-CSF). A sequential production of T helper-1 (Th1) and T helper-2 (Th2) cytokines was induced by BCG. Early, at days 1-2 after stimulation, the response was dominated by monokines and a low IFN-gamma and TNF-beta production. At days 4-5 there was a marked production of Th1 lymphokines, with approximately 6% IFN-gamma+ cells, 4% TNF-beta+ cells and 2% IL-2+ cells. Late in the reaction, at days 10-12, a Th2 response with IL-4, IL-5 and IL-10 was detected, while the synthesis of Th1 lymphokines and monokines declined. Overall, our results provide further evidence of IFN-gamma as the major cytokine induced by mycobacteria in healthy individuals, but also suggest that Th2 cytokines participate in the response.
Sander
B
B
Department of Pathology, Faculty of Health Sciences, University of Linköping, Sweden.
Skansén-Saphir
U
U
Damm
O
O
Håkansson
L
L
Andersson
J
J
Andersson
U
U
D000328:Adult; D000942:Antigens, Bacterial / Q000276:immunology*; D018929:Cell Culture Techniques; D016207:Cytokines / Q000096:biosynthesis*; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007378:Interleukins / Q000096:biosynthesis; D007700:Kinetics; D009163:Mycobacterium bovis / Q000276:immunology*; D012795:Sialoglycoproteins / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000942:Antigens, Bacterial; D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007378:Interleukins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha