T cells can see Mycobacterium tuberculosis. But not terribly well. And researchers from New York University School of Medicine have identified one reason why.

In work published in the Jan. 14, 2016, online issue of Cell Host & Microbe, they reported that the activation of an antigen export pathway that is used by M. tuberculosis-infected dendritic cells to share antigens with uninfected dendritic cells did more harm than good overall.

Such antigen-sharing did enable uninfected as well as infected cells to activate T cells. But because the infected cells activated T cells more strongly, antigen export weakened the overall T-cell response to the bacterium in infected mice.

The results, lead author Smita Srivastava told BioWorld Today, provide "one mechanism – we are not saying it is the only mechanism, but one mechanism" – for the well-known phenomenon of T-cell evasion by M. tuberculosis.

Like HIV, tuberculosis infects some of the very immune system cells that are meant to fight it. In fact, senior author Joel Ernst told BioWorld Today that "a T cell is really not much good without an antigen-presenting cell to tell it what to do. . . . Tuberculosis infects the instructors" of the immune system.

Unlike HIV infection, however, tuberculosis, or TB, infection is not universally fatal in the absence of treatment. Tuberculosis evolved at a time when the global human population was a tiny fraction of today's, and so there was much stronger evolutionary pressure to evolve to co-exist with one's hosts, rather than kill them off.

And so, once TB has established an infection, its typical path is to enter a period of quiescence, dividing minimally and trying to keep a low profile and stay out of the immune system's way.

From the bug's point of view, it's been a highly successful strategy. Globally, 2 billion people are infected with TB, with most of those infections asymptomatic.

The news is not as good for TB's victims. Though the death rate from the disease has dropped by nearly 50 percent since 1990, that drop still translated into 1.5 million deaths in 2014, according to the World Health Organization (WHO).

In 2014, Srivastava and Ernst published work describing an antigen export system that infected dendritic cells used to secrete antigens, which would then be taken up by uninfected bystander dendritic cells. Their assumption at that time was that such antigen-sharing would strengthen the overall T-cell response to M. tuberculosis.

Further experimentation, however, did not bear out that assumption.

In the studies now published in Cell Host & Microbe, Srivastava, who is an associate researcher at New York University, Ernst, a professor of medicine there, and their co-author Patricia Grace showed that the net effect of antigen-sharing was to weaken the overall T-cell response.

The team first identified kinesin as an important host protein in mediating antigen export.

They then knocked down kinesin in dendritic cells, preventing such export, and transferred those cells to mice.

To their surprise, the T-cell response was stronger in mice whose dendritic cells were unable to export M. tuberculosis antigens, suggesting that antigen export actually benefits the bacterium, not the host.

The results underscore how much remains to be learned about the antigen export pathway. Even "antigen export" may be a misnomer.

Ernst said that the antigen export pathway may be used by different pathogens for different ends. Other bacteria and viruses could use the system to infect more cells, or to export toxins. There is some evidence that this is the case for HIV and Salmonella enterica serovar Typhi (the agent of typhoid fever), respectively.

Understanding the system better, he said, might translate into "knowing when we would want to up-regulate it, and when we would want to down-regulate it."

On a practical level, the results provide evidence, albeit extremely early stage evidence, that blocking antigen export could be a pharmacological strategy to strengthen the immune system in its fight against tuberculosis.

Blocking the pathway could possibly shorten the treatment necessary for tuberculosis. That treatment currently takes six months to two years and can be nearly impossible to adhere to in the low-resource settings where tuberculosis is a scourge, increasing the chance for the development of multidrug-resistant and extensively drug-resistant strains.

Blocking antigen export could also be helpful in the fight to develop an effective tuberculosis vaccine.

WHO, which in 2014 announced an ambitious plan to reduce the incidence rate of TB by 90 percent and the death rate by 95 percent by 2035, said to meet those goals, "additional tools must be available by 2025. In particular, a new vaccine that is effective pre- and post-exposure and a safer and more effective treatment for latent TB infection are needed to reduce the number of new TB cases arising from the approximately 2 billion people worldwide who are infected with M. tuberculosis."