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May 16, 2011

T-Cell Responses Against Major Tuberculosis Cell Wall Lipid Hint at Vaccination Strategy

  • Studies focused on monitoring T-cell responses to tuberculosis (TB) infection and treatment  suggest mycobacterial lipids may represent promising targets for TB vaccines. A team led by Ajit Lalvani, Ph.D., of the National Heart and Lung Institute’s Tuberculosis Research Unit, at Imperial College London, found robust populations of IFN-γ- and IL-2-secreting T cells specific for the mycobacterial cell wall lipid mycolic acid (MA) in infected TB patients.

    MA-specific responses dropped dramatically with declining pathogen burden as a result of treatment, but re-exposing T cells taken from cured patients to the MA antigen long after successful therapy led to rapid recall expansion in vitro, indicating lipid-specific immunological memory. The research is reported in the Journal of Clinical Investigation in a paper titled “A mycolic acid–specific CD1-restricted T cell population contributes to acute and memory immune responses in human tuberculosis infection.”

    Although current TB vaccine strategies are largely aimed at activating conventional T-cell responses to mycobacterial protein antigens, the lipid-rich cell wall of Mycobacterium tuberculosis is also essential for pathogenicity and provides other potential targets for unconventional T-cell recognition, Dr. Lalvani and colleagues report.

    The predominant lipid component of the M. tuberculosis cell wall is mycolic acid, which represents a key virulence factor, protecting M. tuberculosis from dehydration, exposure to drugs, and the hostile environment of the macrophage phagolysosome. Free MA is in addition a major component of extracellular biofilms formed by M. tuberculosis that harbor drug-tolerant persisting M. tuberculosis populations.

    However, the researchers note, “the role of lipid-specific T cells in human TB infection remains unclear; in particular, almost nothing is known of their relationship to antigen load in vivo, their ability to home to sites of infection, and whether or not they can establish immunological memory.”

    The U.K.-based researchers have now confirmed the presence of IFN-γ- and IL-2-secreting, CD1b- restricted T cells at the sites of disease in TB patients, albeit at lower concentrations than peptide-specific T cells. Eighty percent of untreated TB patients in an ethnically diverse patient cohort had circulating MA-specific T cells. This prevalence was similar to that of T cells for the highly immunodominant protein antigens ESAT-6 (90%) and CFP10 (80%).

    Curiously, MA-specific T cells were not detectable in BCG-vaccinated healthy controls, whereas T cells responding to total M. tuberculosis lipids and to other defined mucobacterial lipids and peptides are generated as a result of BCG vaccination. This indicates that MA-specific T cells represent a highly specific and sensitive marker of TB and could prove useful for future immunodiagnostics, the authors note.

    Treatment for TB was associated with an obvious decline in lipid-specific T cells, and this drop off generally mirrored the fall in numbers of IFN-γ–secreting T cells against the major mycobacterial peptide antigens ESAT-6 and CFP10. However, the MA-specific T cell decline was more pronounced, the researchers found.

    Although T cells specific to the major mycobacterial peptides persisted in 4/5 patients who had been successfully treated for TB, T cells specific for MA could be detected in only one of the five patients at the same six month time point. Of the four patients evaluated at 12 months, all retained peptide-specific T cells, where as MA-specific T cells were only just detectable in two patients. The authors suggest these finding suggest that MA-specific T cells are more closely dynamically related to pathogen burden than peptide-specific T cells, and represent a better marker of antigen load.

    Importantly, using a cultured ELISpot method for determining the presence of MHC-restricted memory T cells in TB, the researchers confirmed that MA-specific T cells could be expanded from the patients’ blood two years after they had completed curative treatment for TB, suggesting they had retained long-term immunological memory.

    “We believe this is the first study simultaneously to quantify lipid antigen-specific and protein antigen-specific T cells in the same individuals,” the authors note. “Our results establish what we believe is the first time that MA is a major target of circulating unconventional T cells in human TB. Our results therefore highlight the potential for harnessing CD1-restricted T cells by vaccination in humans, making broadly immunogenic antigens such as MA potentially important new components of future subunit vaccines against TB.”


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