A T-Cell Cytokine Channels Tuberculosis into the Latent Form of the Disease

Molecular biologists studying tuberculosis have identified a T-cell surface protein that channels infection by Mycobacterium tuberculosis into the chronic, latent form of the disease rather than into the acute, active form.

Approximately one-third of the world’s population is infected with M. tuberculosis (Mtb). Although most infected people remain asymptomatic, they have a 10% lifetime risk of developing active tuberculosis (TB). The challenge for disease researchers is to identify immune parameters that distinguish individuals with latent TB from those with active TB.

Using human and experimental models of Mtb infection, investigators at the University of Pittsburgh School of Medicine (PA, USA) demonstrated that organized ectopic lymphoid structures containing T-cells expressing the signaling molecule CXCR5 (chemokine (C-X-C motif) receptor 5) were present in Mtb-infected lungs. Mice deficient in CXCR5 had increased susceptibility to TB due to defective T-cell localization within the lung parenchyma.

CXCR5 expression in T-cells mediated correct T-cell localization within TB granulomas, promoted efficient macrophage activation, protected against Mtb infection, and facilitated lymphoid follicle formation.

These findings, which were published in the January 2, 2013, online edition of the Journal of Clinical Investigation, demonstrated that CXCR5+ T cells played a protective role in the immune response against TB and highlighted their potential use for future TB vaccine design and therapy.

"A hallmark of TB that we see on chest X-rays is the granuloma, a collection of immune cells that surround the infected lung cells," said senior author Dr. Shabaana A. Khader, assistant professor of pediatrics at the University of Pittsburgh School of Medicine. "But what we did not know was the difference between a functioning protective granulomae, as in latent TB, and a nonprotective granuloma seen in active TB patients. We aimed to find immunologic markers that could show us the status of the infection."

"The presence of CXCR5 provides a specific address for the infected cells that tells the immune cells where to focus their attention to contain the problem," said Dr. Khader. "That results in the formation of ectopic lymphoid structures and the protective granuloma that keeps TB infection under control, unlike in active disease. Without CXCR5, those structures did not form and active TB was more likely. The protective power of CXCR5 points us in a novel direction for future management of TB. These findings have powerful implications for the development of vaccines to prevent infection."

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University of Pittsburgh School of Medicine