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T-Cell Response to TB Infection: High-Resolution Imaging Reveals Major Differences Between Lab and Live Results

Findings from an NIAID study, appearing online ahead of print in the May 19, 2011, issue of Immunity, provide new insights into how the immune system clears mycobacterial infections and how the behavior of immune cells differs in lab cultures versus living tissues.

Background

Mycobacterium tuberculosis is the bacterium that causes tuberculosis (TB), an airborne disease that leads to the formation in the lungs of immune-cell masses called granulomas. Investigators led by Ronald Germain, M.D., Ph.D., chief of NIAID's Laboratory of Systems Biology, and Alan Sher, Ph.D., chief of NIAID's Laboratory of Parasitic Diseases, used a type of high-resolution imaging called 2-photon intravital microscopy to study TB infection in a mouse model. Intravital microscopy enables researchers to visualize inside the tissues and organs of a living animal how the immune system responds to bacteria and other microbes in real time.

Results of Study

The NIAID investigators used 2-photon intravital microscopy to examine T-cell interactions with other cells in TB granulomas formed in the liver of mice. They found that the majority of T cells migrated rapidly within the granuloma cell mass, but only a small percentage of them stopped and bound to cells bearing antigen, a molecule that triggers an immune response. Previous studies have demonstrated that arrested T-cell movement occurs as a consequence of T-cell activation.

Video screenshot of T-cell arrest within a TB-induced granuloma after antigen exposure.
T-cell arrest within a TB-induced granuloma after antigen exposure.
Video screenshot of cluster of IFN-gamma-producing T cells.
Cluster of IFN-gamma-producing T cells.
 
Video screenshot of antigen-specific and nonspecific T-cell migration within a TB-induced granuloma.
Antigen-specific and nonspecific T-cell migration within a TB-induced granuloma
 

Given the rarity of arrested T cells in the granuloma, the team hypothesized that very few of these cells were actually participating in the antimicrobial response. This finding was unexpected because previous studies performed in the test tube with cells isolated from a living organism showed very robust T-cell responses to mycobacterial antigen.

Further work showed that a very low number of T cells in the granulomas secreted IFN-gamma, a cell-signaling molecule that helps other immune cells kill mycobacteria and is indicative of T cell activation. These results were in stark contrast to experiments conducted by the NIAID team in which large amounts of synthetic TB antigen was administered to the infected animals. Results from these experiments showed that almost all the T cells in the granulomas made the signaling molecule, thereby producing a strong antimicrobial response.

Significance

These findings indicate that only a small percentage of immune cells capable of clearing a mycobacterial infection are active at any one moment during the course of the infection. Although T cells that bind to antigen-presenting cells within TB granulomas make the IFN-gamma needed to fight the microbe, the response is muted. But, based on the team's observations of T-cell behavior in response to synthetic antigen given to the infected animals, it appears that there is a potential for T cells to clear TB infections much more aggressively if more antigen is present to activate the T cells. The difference in results appears to relate to the ability of mycobacteria to limit how much antigen is visible to the T cells in the granuloma. The observations also demonstrate how distinctly cells behave in an artificial lab setting versus a real infected site.

Next Steps

The team's results indicate that strategies aimed at increasing the level of antigen presented in a granuloma may be a promising new direction in therapeutics against TB. Boosting the amount of antigen could improve the bacteria-killing ability of the T cells that take up residence in the granuloma during infection.

References

Egen JE, Rothfuchs AG, Feng CG, Horowitz MA, Sher A, Germain RN. Intravital imaging reveals limited antigen presentation and T cell effector function in mycobacterial granulomas. Immunity. 2011 May 19 [Epub ahead of print].

Dr. Germain's lab page and Dr. Sher's lab pages

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Last Updated December 21, 2011

Last Reviewed June 02, 2011