A CD4+ TNF+ monofunctional memory T-cell response to BCG vaccination is associated with Mycobacterium tuberculosis infection in infants exposed to HIV

• Type of Material: Article
• Authors: Alex J Warr, University of Washington; Christine Anterasian, University of Washington; Javeed A Shah, University of Washington; Stephen C De Rosa, Fred Hutchinson Cancer Research Center; Felicia K Nguyen, University of Washington; Elizabeth Maleche-Obimbo, University of Nairobi; Lisa Cranmer, Emory University; Daniel Matemo, Kenyatta National Hospital; Jerphason Mecha, Kenyatta National Hospital; John Kinuthia, Kenyatta National Hospital; Sylvia M LaCourse, University of Washington; Grace C John-Stewart, University of Washington; Thomas R Hawn, University of Washington
• Language: English
• Date: 2022-06-01
• Publisher: ELSEVIER
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ebiom.2022.104023
• Title of Journal or Parent Work: EBIOMEDICINE
• Volume: 80
• Start Page: 104023
• End Page: 104023
• Grant/Funding Information: This work was supported by the Thrasher Research Fund (to GJS & TRH), NIH/NIAID K23AI120793 to SML, NIH/NIAID K24AI137310 to TRH, NIH K12 HD000850-36 Pediatric Scientist Development Program grant to CA, NIH/Fogarty R25TW009345 to AJW, NIH/NIAID K23AI143479 to LMC, NIH UL1TR000423 for REDCap, and the University of Washington / Fred Hutch Center for AIDS Research (to SCD), an NIH-funded program under award number AI027757 which is supported by the following NIH Institutes and Centers: NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, NIA, NIGMS, NIDDK.
• Keywords: CHILDREN; HIV; Tuberculin test; IMMUNE-RESPONSES; BCG; Research & Experimental Medicine; General & Internal Medicine; Medicine, General & Internal; PREVENTION; T-Lymphocytes; SUBSET; Life Sciences & Biomedicine; Tuberculosis; CHILDHOOD; Medicine, Research & Experimental; Science & Technology; PROTECTION; INTERFERON-GAMMA
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

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: 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: 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: 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: Thrasher Research Fund.