Format

Send to

Choose Destination
Am J Respir Crit Care Med. 2016 Aug 1;194(3):345-55. doi: 10.1164/rccm.201509-1746OC.

Lipoarabinomannan-Responsive Polycytotoxic T Cells Are Associated with Protection in Human Tuberculosis.

Author information

1
1 Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany.
2
2 Division of Clinical Infectious Diseases, German Center for Infection Research, Borstel, Germany.
3
3 Institute for Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
4
4 Harvard School of Public Health, Boston, Massachusetts; and.
5
5 Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, California.

Abstract

RATIONALE:

The development of host-targeted, prophylactic, and therapeutic interventions against tuberculosis requires a better understanding of the immune mechanisms that determine the outcome of infection with Mycobacterium tuberculosis.

OBJECTIVES:

To identify T-cell-dependent mechanisms that are protective in tuberculosis.

METHODS:

Multicolor flow cytometry, cell sorting and growth inhibition assays were employed to compare the frequency, phenotype and function of T lymphocytes from bronchoalveolar lavage or the peripheral blood.

MEASUREMENTS AND MAIN RESULTS:

At two independent study sites, bronchoalveolar lavage cells from donors with latent tuberculosis infection limited the growth of virulent Mycobacterium tuberculosis more efficiently than those in patients who developed disease. Unconventional, glycolipid-responsive T cells contributed to reduced mycobacterial growth because antibodies to CD1b inhibited this effect by 55%. Lipoarabinomannan was the most potent mycobacterial lipid antigen (activation of 1.3% T lymphocytes) and activated CD1b-restricted T cells that limited bacterial growth. A subset of IFN-γ-producing lipoarabinomannan-responsive T cells coexpressed the cytotoxic molecules perforin, granulysin, and granzyme B, which we termed polycytotoxic T cells. Taking advantage of two well-defined cohorts of subjects latently infected with Mycobacterium tuberculosis or patients who developed active disease after infection, we found a correlation between the frequency of polycytotoxic T cells and the ability to control infection (latent tuberculosis infection, 62%; posttuberculosis patients, 26%).

CONCLUSIONS:

Our data define an unconventional CD8(+) T-cell subset (polycytotoxic T cells) that is based on antigen recognition and function. The results link clinical and mechanistic evidence that glycolipid-responsive, polycytotoxic T cells contribute to protection against tuberculosis.

KEYWORDS:

cytotoxicity; glycolipid antigens; infectious immunology; unconventional T cells

PMID:
26882070
PMCID:
PMC5441105
DOI:
10.1164/rccm.201509-1746OC
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center