Production of Proinflammatory Cytokines by CD4+ and CD8+ T Cells in Response to Mycobacterial Antigens among Children and Adults with Tuberculosis

Author:

Morrow Erin1,Liu Qijia2,Kiguli Sarah3ORCID,Swarbrick Gwendolyn4ORCID,Nsereko Mary5,Null Megan D.4,Cansler Meghan4,Mayanja-Kizza Harriet56ORCID,Boom W. Henry57,Chheng Phalkun5,Nyendak Melissa R.8,Lewinsohn David M.89,Lewinsohn Deborah A.4,Lancioni Christina L.4

Affiliation:

1. School of Medicine, Oregon Health and Science University, Portland, OR 97239, USA

2. School of Public Health, Oregon Health and Science University, Portland, OR 97239, USA

3. Department of Pediatrics, Makerere University, Mulago Hill Road, Kampala P.O. Box 7072, Uganda

4. Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA

5. Uganda-Case Western Research Collaboration, Case Western Reserve University, Cleveland, OH 44106, USA

6. Department of Medicine, Makerere University, Mulago Hill Road, Kampala P.O. Box 7072, Uganda

7. Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA

8. Department of Medicine, Oregon Health and Science University, Portland, OR 97239, USA

9. Division of Pulmonary and Critical Care Medicine, Portland VA Medical Center, Portland, OR 97239, USA

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of pediatric morbidity and mortality. Young children are at high risk of TB following Mtb exposure, and this vulnerability is secondary to insufficient host immunity during early life. Our primary objective was to compare CD4+ and CD8+ T-cell production of proinflammatory cytokines IFN-gamma, IL-2, and TNF-alpha in response to six mycobacterial antigens and superantigen staphylococcal enterotoxin B (SEB) between Ugandan adults with confirmed TB (n = 41) and young Ugandan children with confirmed (n = 12) and unconfirmed TB (n = 41), as well as non-TB lower respiratory tract infection (n = 39). Flow cytometry was utilized to identify and quantify CD4+ and CD8+ T-cell cytokine production in response to each mycobacterial antigen and SEB. We found that the frequency of CD4+ and CD8+ T-cell production of cytokines in response to SEB was reduced in all pediatric cohorts when compared to adults. However, T-cell responses to Mtb-specific antigens ESAT6 and CFP10 were equivalent between children and adults with confirmed TB. In contrast, cytokine production in response to ESAT6 and CFP10 was limited in children with unconfirmed TB and absent in children with non-TB lower respiratory tract infection. Of the five additional mycobacterial antigens tested, PE3 and PPE15 were broadly recognized regardless of TB disease classification and age. Children with confirmed TB exhibited robust proinflammatory CD4+ and CD8+ T-cell responses to Mtb-specific antigens prior to the initiation of TB treatment. Our findings suggest that adaptive proinflammatory immune responses to Mtb, characterized by T-cell production of IFN-gamma, IL-2, and TNF-alpha, are not impaired during early life.

Funder

NIH

Papé Family Research Institute

CWRU Tuberculosis Research Unit

Publisher

MDPI AG

Subject

Infectious Diseases,Microbiology (medical),General Immunology and Microbiology,Molecular Biology,Immunology and Allergy

Reference52 articles.

1. Barr, L. (2023, September 01). Tuberculosis Research Funding Trends, 2005–2018. 2019. Tuberculosis Research Funding Trends. Available online: https://www.treatmentactiongroup.org/wp-content/uploads/2019/12/tbrd_2019_web.pdf.

2. World Health Organization (2023, September 01). Global Tuberculosis Report 2020. 2020. Global Tuberculosis Report. 15 October 2020. Available online: https://www.who.int/publications/i/item/9789240013131.

3. The global burden of tuberculosis mortality in children: A mathematical modelling study;Dodd;Lancet Glob. Health,2017

4. What We Know About Tuberculosis Transmission: An Overview;Churchyard;J. Infect. Dis.,2017

5. The natural history of childhood intra-thoracic tuberculosis: A critical review of literature from the pre-chemotherapy era;Marais;Int. J. Tuberc. Lung Dis.,2004

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