Mycolactone Suppresses T Cell Responsiveness by Altering Both Early Signaling and Posttranslational Events

Abstract

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.

Mycolactone impairs T cell homing by suppressing microRNA control of L-selectin expression

“…Since mycolactone displays cytopathic effects in vitro (10), we assessed T-cell viability in mycolactoneinjected mice. Confirming our previous studies showing that primary T cells are relatively resistant to mycolactone cytotoxicity (6), no evidence of enhanced apoptosis could be demonstrated by flow-cytometric analysis of T cells in peripheral blood, PLNs and spleen, or by staining of LN sections (Fig. S1).…”

“…Mycolactone was known to block the capacity of primary T cells to produce multiple cytokines upon activation (2,6). Here, we show that mycolactone also impairs their migratory properties.…”

“…The immune profiling of patients has recently revealed systemic defects in the production of multiple T-cell cytokines, suggesting that mycolactone impairs the generation of cellular responses (2). In line with this hypothesis, mycolactone was reported to suppress the production of various cytokines by monocytes, lymphocytes, and dendritic cells (DCs) in vitro (3)(4)(5)(6). The mechanism by which mycolactone modulates protein expression in a geneand cell-specific manner nevertheless remains mysterious, as differently from known immunosuppressants, mycolactone acts independently of the mammalian target of rapamycin (mTOR).…”

Suppressive effect of mycolactone-containing fraction from Mycobacterium ulcerans on antibody production against co-administered antigens

“…In addition, several in vitro studies have suggested that mycolactone could inhibit cytokine and chemokine production from immune cells such as T cells, macrophages, and dendritic cells [9][10][11][12][13]. These observations clearly suggested that mycolactone presents immunosuppressive effects and may have an important role in the successful infection of M. ulcerans in humans.…”

“…Injection of mycolactone into guinea pig produced an ulcer similar to Buruli ulcer [4]. Mycolactone inhibits the production of various cytokines, chemokines, and other secreted immune modulators [7] from immune cells such as monocytes [8], macrophages [9], dendritic cells [10], and T cells [11][12][13]. When a mycolactone-deficient strain of M. ulcerans was injected into model animals, a granuloma was successfully developed and the bacteria were cleared from the infected regions [14,15], suggesting that mycolactone has a suppressive effect on cell-mediated immune responses.…”