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Characterizing Early T Cell Responses in Nonhuman Primate Model of Tuberculosis

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading infectious disease killer worldwide with 1.4 million TB deaths in 2019. While the majority of infected population maintain an active control of the bacteria, a subset develops active disease leading to mortality. Effect...

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Autores principales: Sharan, Riti, Singh, Dhiraj Kumar, Rengarajan, Jyothi, Kaushal, Deepak
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416058/
https://www.ncbi.nlm.nih.gov/pubmed/34484203
http://dx.doi.org/10.3389/fimmu.2021.706723
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author Sharan, Riti
Singh, Dhiraj Kumar
Rengarajan, Jyothi
Kaushal, Deepak
author_facet Sharan, Riti
Singh, Dhiraj Kumar
Rengarajan, Jyothi
Kaushal, Deepak
author_sort Sharan, Riti
collection PubMed
description Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading infectious disease killer worldwide with 1.4 million TB deaths in 2019. While the majority of infected population maintain an active control of the bacteria, a subset develops active disease leading to mortality. Effective T cell responses are critical to TB immunity with CD4(+) and CD8(+) T cells being key players of defense. These early cellular responses to TB infection have not yet been studied in-depth in either humans or preclinical animal models. Characterizing early T cell responses in a physiologically relevant preclinical model can provide valuable understanding of the factors that control disease development. We studied Mtb-specific T cell responses in the lung compartment of rhesus macaques infected with either a low- or a high-dose of Mtb CDC1551 via aerosol. Relative to baseline, significantly higher Mtb-specific CD4(+)IFN-γ(+) and TNF-α (+) T cell responses were observed in the BAL of low dose infected macaques as early as week 1 post TB infection. The IFN-γ and TNF-a response was delayed to week 3 post infection in Mtb-specific CD4(+) and CD8(+)T cells in the high dose group. The manifestation of earlier T cell responses in the group exposed to the lower Mtb dose suggested a critical role of these cytokines in the antimycobacterial immune cascade, and specifically in the granuloma formation to contain the bacteria. However, a similar increase was not reflected in the CD4(+) and CD8(+)IL-17(+) T cells at week 1 post infection in the low dose group. This could be attributed to either a suppression of the IL-17 response or a lack of induction at this early stage of infection. On the contrary, there was a significantly higher IL-17(+) response in Mtb-specific CD4(+) and CD8(+)T cells at week 3 in the high dose group. The results clearly demonstrate an early differentiation in the immunity following low dose and high dose infection, largely represented by differences in the IFN-γ and TNF-α response by Mtb-specific T cells in the BAL. This early response to antigen expression by the bacteria could be critical for both bacterial growth control and bacterial containment.
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spelling pubmed-84160582021-09-04 Characterizing Early T Cell Responses in Nonhuman Primate Model of Tuberculosis Sharan, Riti Singh, Dhiraj Kumar Rengarajan, Jyothi Kaushal, Deepak Front Immunol Immunology Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading infectious disease killer worldwide with 1.4 million TB deaths in 2019. While the majority of infected population maintain an active control of the bacteria, a subset develops active disease leading to mortality. Effective T cell responses are critical to TB immunity with CD4(+) and CD8(+) T cells being key players of defense. These early cellular responses to TB infection have not yet been studied in-depth in either humans or preclinical animal models. Characterizing early T cell responses in a physiologically relevant preclinical model can provide valuable understanding of the factors that control disease development. We studied Mtb-specific T cell responses in the lung compartment of rhesus macaques infected with either a low- or a high-dose of Mtb CDC1551 via aerosol. Relative to baseline, significantly higher Mtb-specific CD4(+)IFN-γ(+) and TNF-α (+) T cell responses were observed in the BAL of low dose infected macaques as early as week 1 post TB infection. The IFN-γ and TNF-a response was delayed to week 3 post infection in Mtb-specific CD4(+) and CD8(+)T cells in the high dose group. The manifestation of earlier T cell responses in the group exposed to the lower Mtb dose suggested a critical role of these cytokines in the antimycobacterial immune cascade, and specifically in the granuloma formation to contain the bacteria. However, a similar increase was not reflected in the CD4(+) and CD8(+)IL-17(+) T cells at week 1 post infection in the low dose group. This could be attributed to either a suppression of the IL-17 response or a lack of induction at this early stage of infection. On the contrary, there was a significantly higher IL-17(+) response in Mtb-specific CD4(+) and CD8(+)T cells at week 3 in the high dose group. The results clearly demonstrate an early differentiation in the immunity following low dose and high dose infection, largely represented by differences in the IFN-γ and TNF-α response by Mtb-specific T cells in the BAL. This early response to antigen expression by the bacteria could be critical for both bacterial growth control and bacterial containment. Frontiers Media S.A. 2021-08-17 /pmc/articles/PMC8416058/ /pubmed/34484203 http://dx.doi.org/10.3389/fimmu.2021.706723 Text en Copyright © 2021 Sharan, Singh, Rengarajan and Kaushal https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Sharan, Riti
Singh, Dhiraj Kumar
Rengarajan, Jyothi
Kaushal, Deepak
Characterizing Early T Cell Responses in Nonhuman Primate Model of Tuberculosis
title Characterizing Early T Cell Responses in Nonhuman Primate Model of Tuberculosis
title_full Characterizing Early T Cell Responses in Nonhuman Primate Model of Tuberculosis
title_fullStr Characterizing Early T Cell Responses in Nonhuman Primate Model of Tuberculosis
title_full_unstemmed Characterizing Early T Cell Responses in Nonhuman Primate Model of Tuberculosis
title_short Characterizing Early T Cell Responses in Nonhuman Primate Model of Tuberculosis
title_sort characterizing early t cell responses in nonhuman primate model of tuberculosis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416058/
https://www.ncbi.nlm.nih.gov/pubmed/34484203
http://dx.doi.org/10.3389/fimmu.2021.706723
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