Mycolactone suppresses T cell responsiveness by altering both early signaling and posttranslational events.
Mycolactone is a diffusible lipid toxin produced by Mycobacterium ulcerans, the causative agent of a necrotizing skin disease referred to as Buruli ulcer. Intriguingly, patients with progressive lesions display a systemic suppression of Th1 responses that resolves on surgical excision of infected tissues. In this study, we examined the effects of mycolactone on the functional biology of T cells and identified two mechanisms by which mycolactone suppresses cell responsiveness to antigenic stimulation. At noncytotoxic concentrations, mycolactone blocked the activation-induced production of cytokines by a posttranscriptional, mammalian target of rapamycin, and cellular stress-independent mechanism. In addition, mycolactone triggered the lipid-raft association and activation of the Src-family kinase, Lck. Mycolactone-mediated hyperactivation of Lck resulted in the depletion of intracellular calcium stores and downregulation of the TCR, leading to impaired T cell responsiveness to stimulation. These biochemical alterations were not observed when T cells were exposed to other bacterial lipids, or to structurally related immunosuppressors. Mycolactone thus constitutes a novel type of T cell immunosuppressive agent, the potent activity of which may explain the defective cellular responses in Buruli ulcer patients.
Boulkroun
Sheerazed
S
Unité Postulante Pathogénomique Mycobactérienne Intégrée, Institut Pasteur, Paris, France.
Guenin-Macé
Laure
L
Thoulouze
Maria-Isabel
MI
Monot
Marc
M
Merckx
Anaïs
A
Langsley
Gordon
G
Bismuth
Georges
G
Di Bartolo
Vincenzo
V
Demangel
Caroline
C
D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology* / Q000633:toxicity; D054312:Buruli Ulcer / Q000201:enzymology / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000633:toxicity; D007424:Intracellular Fluid / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018942:Macrolides; D051379:Mice; D008810:Mice, Inbred C57BL; D019911:Mycobacterium ulcerans / Q000276:immunology; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D013997:Time Factors
D001427:Bacterial Toxins; D007166:Immunosuppressive Agents; D018942:Macrolides; C117218:mycolactone; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)