A CD4+ TNF+ monofunctional memory T-cell response to BCG vaccination is associated with Mycobacterium tuberculosis infection in infants exposed to HIV.
Antitubercular Agents
/ administration & dosage
BCG Vaccine
/ administration & dosage
CD4-Positive T-Lymphocytes
/ drug effects
Cytokines
/ immunology
HIV Infections
/ immunology
Humans
Infant
Infant, Newborn
Isoniazid
/ administration & dosage
Memory T Cells
/ drug effects
Mycobacterium tuberculosis
Tuberculosis
/ diagnosis
Tumor Necrosis Factor-alpha
/ immunology
BCG
HIV
T-Lymphocytes
Tuberculin test
Tuberculosis
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Jun 2022
Jun 2022
Historique:
received:
14
09
2021
revised:
20
03
2022
accepted:
09
04
2022
pubmed:
10
5
2022
medline:
15
6
2022
entrez:
9
5
2022
Statut:
ppublish
Résumé
The immunologic correlates of risk of Mycobacterium tuberculosis (Mtb) infection after BCG vaccination are unknown. The mechanism by which BCG influences the tuberculin skin test (TST) remains poorly understood. We evaluated CD4+ T-cell responses in infants exposed to HIV and uninfected (HEU) who received BCG at birth and examined their role in susceptibility to Mtb infection and influence on TST induration. HEU infants were enrolled in a randomised clinical trial of isoniazid (INH) to prevent Mtb infection in Kenya. We measured mycobacterial antigen-specific Th1 and Th17 cytokine responses at 6-10 weeks of age prior to INH randomisation and compared responses between Mtb infected and uninfected infants. Outcomes at 14 months of age included TST, QuantiFERON-Plus (QFT-Plus), and ESAT-6/CFP-10-specific non-IFN-γ cytokines measured in QFT-Plus supernatants. A monofunctional mycobacterial antigen-specific TNF+ CD4+ effector memory (CCR7-CD45RA-) T-cell response at 6-10 weeks of age was associated with Mtb infection at 14 months of age as measured by ESAT-6/CFP-10-specific IFN-γ and non-IFN-γ responses (Odds Ratio 2.26; Confidence Interval 1.27-4.15; P = 0.006). Mycobacterial antigen-specific polyfunctional effector memory Th1 responses at 6-10 weeks positively correlated with TST induration in infants without evidence of Mtb infection at 14 months, an association which was diminished by INH therapy. Induction of monofunctional TNF+ CD4+ effector memory T-cell responses may be detrimental in TB vaccine development. This study also provides mechanistic insight into the association of BCG-induced immune responses with TST induration and further evidence that TST-based diagnoses of Mtb infection in infants are imprecise. Thrasher Research Fund.
Sections du résumé
BACKGROUND
BACKGROUND
The immunologic correlates of risk of Mycobacterium tuberculosis (Mtb) infection after BCG vaccination are unknown. The mechanism by which BCG influences the tuberculin skin test (TST) remains poorly understood. We evaluated CD4+ T-cell responses in infants exposed to HIV and uninfected (HEU) who received BCG at birth and examined their role in susceptibility to Mtb infection and influence on TST induration.
METHODS
METHODS
HEU infants were enrolled in a randomised clinical trial of isoniazid (INH) to prevent Mtb infection in Kenya. We measured mycobacterial antigen-specific Th1 and Th17 cytokine responses at 6-10 weeks of age prior to INH randomisation and compared responses between Mtb infected and uninfected infants. Outcomes at 14 months of age included TST, QuantiFERON-Plus (QFT-Plus), and ESAT-6/CFP-10-specific non-IFN-γ cytokines measured in QFT-Plus supernatants.
FINDINGS
RESULTS
A monofunctional mycobacterial antigen-specific TNF+ CD4+ effector memory (CCR7-CD45RA-) T-cell response at 6-10 weeks of age was associated with Mtb infection at 14 months of age as measured by ESAT-6/CFP-10-specific IFN-γ and non-IFN-γ responses (Odds Ratio 2.26; Confidence Interval 1.27-4.15; P = 0.006). Mycobacterial antigen-specific polyfunctional effector memory Th1 responses at 6-10 weeks positively correlated with TST induration in infants without evidence of Mtb infection at 14 months, an association which was diminished by INH therapy.
INTERPRETATION
CONCLUSIONS
Induction of monofunctional TNF+ CD4+ effector memory T-cell responses may be detrimental in TB vaccine development. This study also provides mechanistic insight into the association of BCG-induced immune responses with TST induration and further evidence that TST-based diagnoses of Mtb infection in infants are imprecise.
FUNDING
BACKGROUND
Thrasher Research Fund.
Identifiants
pubmed: 35533496
pii: S2352-3964(22)00207-9
doi: 10.1016/j.ebiom.2022.104023
pmc: PMC9092381
pii:
doi:
Substances chimiques
Antitubercular Agents
0
BCG Vaccine
0
Cytokines
0
Tumor Necrosis Factor-alpha
0
Isoniazid
V83O1VOZ8L
Types de publication
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
104023Subventions
Organisme : NIAID NIH HHS
ID : K08 AI163381
Pays : United States
Organisme : NICHD NIH HHS
ID : K12 HD000850
Pays : United States
Organisme : NIAID NIH HHS
ID : K23 AI143479
Pays : United States
Organisme : NIAID NIH HHS
ID : P30 AI027757
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
Références
AIDS. 2014 Jun 19;28(10):1421-30
pubmed: 24785950
Tuberculosis (Edinb). 2017 Jul;105:108-112
pubmed: 28610781
Clin Exp Immunol. 2012 Sep;169(3):213-9
pubmed: 22861360
Int J Tuberc Lung Dis. 2006 Nov;10(11):1192-204
pubmed: 17131776
J Infect Dis. 2012 Apr 1;205(7):1035-42
pubmed: 22396610
Nat Biotechnol. 2015 Jun;33(6):610-6
pubmed: 26006008
Am J Respir Crit Care Med. 2010 Oct 15;182(8):1073-9
pubmed: 20558627
Immunity. 2018 Feb 20;48(2):214-226
pubmed: 29466754
Vaccine. 2015 Feb 4;33(6):796-804
pubmed: 25529292
Sci Rep. 2018 Oct 17;8(1):15309
pubmed: 30333506
N Engl J Med. 2011 Jul 7;365(1):21-31
pubmed: 21732834
J Acquir Immune Defic Syndr. 2014 Jul 1;66(3):245-255
pubmed: 24732876
J Infect Dis. 2000 May;181(5):1590-7
pubmed: 10823758
BMJ Open. 2020 Jan 21;10(1):e034308
pubmed: 31969368
Nat Rev Immunol. 2008 Apr;8(4):247-58
pubmed: 18323851
J Immunol. 2014 Apr 1;192(7):2965-9
pubmed: 24591367
Clin Infect Dis. 2021 Jul 15;73(2):e337-e344
pubmed: 32564076
PLoS One. 2010 Aug 19;5(8):e12287
pubmed: 20808814
Clin Infect Dis. 2014 Feb;58(4):470-80
pubmed: 24336911
Pediatr Infect Dis J. 2021 Oct 1;40(10):922-929
pubmed: 34525006
Thorax. 2016 Oct;71(10):932-9
pubmed: 27335104
Microbiol Mol Biol Rev. 2014 Dec;78(4):650-71
pubmed: 25428938
N Engl J Med. 2018 Jul 12;379(2):138-149
pubmed: 29996082
EBioMedicine. 2018 Jan;27:27-39
pubmed: 29249639
Lancet Infect Dis. 2017 Mar;17(3):285-295
pubmed: 27964822
Pediatr Infect Dis J. 2016 May;35(5):524-9
pubmed: 26771662
Vaccine. 2014 Dec 5;32(51):6911-6918
pubmed: 25444816
J Exp Med. 2007 Jun 11;204(6):1405-16
pubmed: 17535971
Nat Commun. 2016 Apr 12;7:11290
pubmed: 27068708
Int J Tuberc Lung Dis. 2011 Aug;15(8):1018-32
pubmed: 21669030
Cell Host Microbe. 2018 Jul 11;24(1):34-42
pubmed: 30001523