Differential skewing of donor-unrestricted and γδ T cell repertoires in tuberculosis-infected human lungs
Paul Ogongo, … , Alasdair Leslie, Samuel M. Behar
Paul Ogongo, … , Alasdair Leslie, Samuel M. Behar
Published November 25, 2019
Citation Information: J Clin Invest. 2020;130(1):214-230. https://doi.org/10.1172/JCI130711.
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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 1

TCR sequences from human TB granulomas.

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TCR sequences from human TB granulomas. (A) Representative immunohistolo...
(A) Representative immunohistology images of lung tissue from an HIVneg subject with active TB (original magnification, ×600) showing CD4+ve and CD8+ve T cells and CD68+ve macrophages. Samples from type A tissue, the most diseased area of the resected lung, had classic caseous granulomas with a distinct lymphocyte cuff and lymphocyte aggregates. Samples from types B and C, from less diseased tissue, show lymphocytic infiltrations and uninvolved alveoli. (B) Number of unique productive TCRα and TCRδ rearrangements obtained from deep-level (blood) or survey-level (lung) sequencing. Each point represents a unique subject. Color identifies the clinical status, grouped by tissue and lung lesion type (i.e., type A, B, or C). (C) Number of unique productive rearrangements obtained from blood or lung tissue from HIVneg versus seropositive subjects (HIVpos) with active or prior TB. (D) Clonality of the productive TCRα and TCRδ rearrangements (as in B). (E) Productive clonality calculated for TCRs identified in blood or lung from HIVneg versus HIVpos subjects with active or prior TB. (F) Effect of HIV status on TCR clonality during active TB. Error bars indicate the median. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by Kruskal-Wallis 1-way ANOVA with Dunn’s multiple comparisons test (B–F).