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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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Research Article Immunology Infectious disease

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

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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 8

Enriched and abundant TCRδ clonotypes.

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Enriched and abundant TCRδ clonotypes.
(A) Distribution of CDR3δ lengths...
(A) Distribution of CDR3δ lengths based on the relative frequency (left) or abundance (right) of all unique clonotypes in blood (top row), lung (middle row), or 92 enriched and abundant clonotypes in the lung (bottom row). Data represent the mean ± SEM. (B) Pairing of Vδ1, Vδ2, or Vδ3 with Jδ1, Jδ2, Jδ3, or Jδ4 gene segments for 92 lung-enriched and abundant TCRδ clonotypes. (C) CDR3δ motif for TCRδ clonotypes with a CDR3δ length of 19 aa. (D) Distribution of the 92 TCRδ clonotypes between HIVneg or HIVpos subjects with active TB. The numbers indicate unique clonotypes. (E) Sharing of unique CDR3δ DNA rearrangements among the 88 blood and lung samples that encoded each unique clonotype. (F) Shared clonotypes between different subjects and their relative abundance. Data represent the mean ± SEM.
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