Editors' ChoiceTuberculosis

Hiding in plain sight

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Science Translational Medicine  27 Jan 2016:
Vol. 8, Issue 323, pp. 323ec13
DOI: 10.1126/scitranslmed.aaf0865

Over millennia of coevolution, Mycobacterium tuberculosis has mastered the art of evading and manipulating the immune defenses of its human host. In the lungs, M. tuberculosis infects and replicates in antigen-presenting cells (APCs), key activators of the adaptive immune response. APCs are the beat cops of the immune system, constantly on patrol. They pick up random extracellular debris, breaking down the proteins into small pieces for cell-surface display and recognition as foreign by T cells. These activated T cells then trigger a cascade of immune responses specifically honed against the pathogen from which the foreign proteins are derived.

M. tuberculosis has evolved complex mechanisms by which it can hide and reproduce in the same APCs whose job it is to kill it, chop it up, and display its parts, essentially by subverting those very processes from the inside. Nevertheless, M. tuberculosis-infected APCs can secrete antigens to be picked up and displayed by uninfected bystander APCs instead, seemingly finding a way around the many intracellular roadblocks that M. tuberculosis has put up to prevent their induction of a specific adaptive immune response. However, new research from Srivastava et al. suggests that even this apparent host victory benefits M. tuberculosis in the end.

In infected APCs, the authors observed M. tuberculosis proteins in discrete cellular compartments called “antigen export vesicles” (AEVs), which were actively exported out of infected APCs. Surprisingly, they found that the uninfected bystander APCs that picked up and displayed the exported antigens were not as good at activating M. tuberculosis–specific T cells as were infected APCs, in which antigen export was prevented and thus, antigen display enhanced. Antigen transfer from infected to uninfected APCs seems like a host strategy to get around the impediments to antigen processing and display that M. tuberculosis sets up in infected cells; however, for M. tuberculosis, it may just be the lesser of two evils to have its immune-stimulating antigens shunted from a more host-beneficial pathway into a less effective one—essentially, by hiding in plain sight.

It is not yet clear whether APCs normally produce AEVs or AEV formation is specifically induced by M. tuberculosis (and perhaps other pathogens) as a means of preventing its “home” APC from displaying antigens that might attract undue immune attention. Still, understanding more about the myriad ways in which M. tuberculosis evades and co-opts the human immune system will be critical in designing vaccines that can stimulate a protective response against this enduring and wily foe.

S. Srivastava et al., Antigen export reduces antigen presentation and limits T cell control of M. tuberculosis. Cell Host Microbe 19, 44–54 (2016). [PubMed]

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