Differential skewing of donor-unrestricted and γδ T cell repertoires in tuberculosis-infected human lungs
Paul Ogongo, Adrie J.C. Steyn, Farina Karim, Kaylesh J. Dullabh, Ismael Awala, Rajhmun Madansein, Alasdair Leslie, Samuel M. Behar
Paul Ogongo, Adrie J.C. Steyn, Farina Karim, Kaylesh J. Dullabh, Ismael Awala, Rajhmun Madansein, Alasdair Leslie, Samuel M. Behar
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Research Article Immunology Infectious disease

Differential skewing of donor-unrestricted and γδ T cell repertoires in tuberculosis-infected human lungs

Abstract

Unconventional T cells that recognize mycobacterial antigens are of great interest as potential vaccine targets against tuberculosis (TB). This includes donor-unrestricted T cells (DURTs), such as mucosa-associated invariant T cells (MAITs), CD1-restricted T cells, and γδ T cells. We exploited the distinctive nature of DURTs and γδ T cell receptors (TCRs) to investigate the involvement of these T cells during TB in the human lung by global TCR sequencing. Making use of surgical lung resections, we investigated the distribution, frequency, and characteristics of TCRs in lung tissue and matched blood from individuals infected with TB. Despite depletion of MAITs and certain CD1-restricted T cells from the blood, we found that the DURT repertoire was well preserved in the lungs, irrespective of disease status or HIV coinfection. The TCRδ repertoire, in contrast, was highly skewed in the lungs, where it was dominated by Vδ1 and distinguished by highly localized clonal expansions, consistent with the nonrecirculating lung-resident γδ T cell population. These data show that repertoire sequencing is a powerful tool for tracking T cell subsets during disease.

Authors

Paul Ogongo, Adrie J.C. Steyn, Farina Karim, Kaylesh J. Dullabh, Ismael Awala, Rajhmun Madansein, Alasdair Leslie, Samuel M. Behar

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Figure 3

CD1-restricted T cells in blood and lung during active TB.

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CD1-restricted T cells in blood and lung during active TB. (A) The frequ...
(A) The frequency of iNKTs in blood (open circles) compared with lung (solid circles) among 5 clinical populations. (B) iNKT cell frequency in paired lung and blood samples, stratified by HIV status for subjects with active TB. Each line represents a single individual. (C) Using a consensus definition of GEM TCRα (Vα1-02, Jα9, CDR3α=CAV(R/L)xTGGFKTIF), GEMs were identified in lung tissue. The 6 most frequently detected clonotypes are shown, with their total relative abundance in the aggregated lung TCR data set. (D) Frequency of GEMs in blood (open circles) versus lung tissue (solid circles) among 5 clinical populations. (E) Clonotypes encoded by TRAV01-2 with the CDR3α CAV(R/L)xTGGFKTIF were identified in HCs (blood, top) and subjects in the lung cohort (blood, second graph; lung, third graph). Non–TRAV01-2 clonotypes encoding the CAV(R/L)xTGGFKTIF CDR3α were identified in lung (bottom graph). A frequency of 0.0000001 was assigned to clonotypes not detected. Dotted lines indicate a productive frequency of 0.05%. Colored violins indicate the most frequently detected lung clonotypes. Red lines indicate the median and blue lines the quartiles.