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T Cell Receptor Repertoire Analysis Points to Potential Tuberculosis Vaccine Targets

NEW YORK — By surveying how certain T cells respond to infection with Mycobacterium tuberculosis, a team of South African researchers has uncovered potential tuberculosis vaccine targets.

Antigen-specific CD4+ T cells are needed to generate protective immunity against M. tuberculosis. In their new study, appearing Thursday in Nature Medicine, researchers from the University of Cape Town and elsewhere used single-cell and bulk T-cell receptor (TCR) sequencing to catalog TCRs expressed by T cells that react to mycobacteria. By comparing differences between individuals exposed to M. tuberculosis who progressed to TB and those who did not, the researchers homed in on antigens that could form the basis of a future vaccine.

"[T]he present study has provided an initial list of TCR specificities and a large TCR sequence database that can be used as a valuable tool in the search for candidate TB vaccine antigens," the researchers wrote in their paper.

Using blood samples from the Adolescent Cohort Study, a large, longitudinal, epidemiological study of TB, the researchers first exposed the samples to M. tuberculosis lysate to tease out mycobacteria-reactive T cells via single-cell TCR sequencing and further sort them into CD4+ or CD8+ T cells. In all, they captured the TCR alpha-beta repertoire from blood samples of 35 individuals who progressed to TB following exposure and 35 individuals who did not. For both groups, more than 90 percent of the sorted M. tuberculosis lysate-reactive T cells were CD4+ T cells, as previous studies had indicated.

The researchers bundled the CDR3beta sequences from the M. tuberculosis lysate-reactive CD4+ T cells from their study with previously published datasets for a total of 25,256 CDR3beta sequences, which they then compared to bulk TCR data generated from blood and lung samples from another cohort of TB patients. The M. tuberculosis lysate-reactive TCR sequences were enriched in lung tissue compared to corresponding blood samples, the researchers found.

Using the Grouping of Lymphocyte Interactions by Paratope Hotspots (GLIPH2) clustering approach, they homed in on sets of TCR similarity groups that all recognize the same epitope. After filtering out rare groups, they focused on a set of about 175 TCR similarity groups that were further associated with certain HLA alleles.

Some of these groups showed ties to controlled TB infection, while others were linked to disease progression.

Through an antigen screen, the investigators then identified the antigens and epitopes targeted by these TCR similarity groups. "We propose that antigens recognized by T cell similarity groups associated with control of infection can be considered as high-priority targets for future vaccine development," they wrote.

In particular, they uncovered two epitopes — PE13 and CFP-10 — that are recognized by T-cell clones that were enriched among controllers. PE13, the researchers noted, is a virulence factor, while CFP-10 is an immunodominant antigen that is specific to M. tuberculosis and is used in tests to identify people with M. tuberculosis infections.

The researchers additionally identified EspA, an epitope that is recognized by T-cell clonotypes enriched among TB progressors.

"Although the authors suggest that PE13 and CFP-10 should be considered for inclusion in subunit vaccines for TB, more work is needed in broader populations before we can decisively conclude that PE13 and CFP-10 are 'good' antigens for TB vaccines," Paul Ogongo from University of California, San Francisco and the Institute of Primate Research in Kenya and Joel Ernst from UCSF wrote in a related Nature Medicine commentary.

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