Investigating the effect of HIV infection on TCR repertoire diversity and Mycobacterium tuberculosis-specific T cell function in Malawian adults

Chimbayo, Elizabeth Tchaiwe (2025) Investigating the effect of HIV infection on TCR repertoire diversity and Mycobacterium tuberculosis-specific T cell function in Malawian adults. PhD thesis, University of Glasgow.

Abstract

The burden of tuberculosis (TB) is huge, posing a significant health threat worldwide, particularly in HIV-endemic regions such as sub-Saharan Africa. Coinfection with HIV is a major risk factor for development and progression to active Mycobacterium tuberculosis (Mtb) disease. People living with HIV (PLHIV) remain at more risk of developing lower respiratory tract infections including TB than HIVuninfected individuals, despite successful coverage of antiretroviral therapy (ART). HIV depletes and impairs the function of Mtb-specific T cells crucial in controlling Mtb infection. However, the impact of HIV on T cell receptor (TCR) usage in alveolar T cells is incompletely described. Characterisation of TCR repertoire is essential for understanding the mechanisms of recognition and control of Mtb infections by T cell adaptive immunity.

To investigate the Mtb antigen-specific TCR diversity and clonality in the airway and blood and assess the impact of HIV and ART on TCR diversity, peripheral blood and bronchoalveolar lavage (BAL) samples were collected from PLHIV ART–naïve, on ART (≥3 years) and HIV-uninfected adults recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Alveolar and peripheral blood lymphocytes were stimulated with Mtb antigens and analysed using flow cytometry and TCR bulk sequencing.

Notably, Mtb-specific TCR repertoires from PLHIV displayed a reduced diversity and clonality compared to HIV-uninfected individuals in both the airway and blood. Moreover, ART was associated with the restoration of TCR clonotypes in PLHIV. Additionally, lower frequencies of Mtb-specific CD4 IFN-γ and TNF-α producing cells were observed in both blood and airway in PLHIV on ART and ART naïve compared to HIV-uninfected individuals. Significant alterations in TCR Vβ expression patterns were noted in CD4+ T cells in PLHIV compared to healthy controls. Vβ1, Vβ7.2, and Vβ23 were higher, while Vβ9 and Vβ18 were lower in blood and airway in PLHIV than in HIV uninfected individuals. In CD8 T cells, no significant differences were found in TCR Vβ expression in the PBMC compared to BAL. However, in the lung, Vβ5.1, Vβ16, and Vβ17 were increased, while Vβ14 was decreased in PLHIV. Furthermore, CDR3 length distribution analysis showed a higher and more diverse distribution of TCR amino acid lengths of Mtb-specific T cells in BAL and PBMCs in HIV-uninfected individuals compared to PLHIV. The elevated TCR Vβ in the lung and blood in PLHIV suggests their potential involvement in HIV immune response whilst depletion of certain TCR Vβ clones in Mtb-specific CD4 and CD8 T cells in the lung and blood may indicate HIV-induced alteration in the repertoire associated with increased TB risk.

These findings suggest a more restricted TCR repertoire in PLHIV compared to healthy controls, with alterations in the frequency of certain families that may impact antigen recognition and specificity. This could lead to a reduced ability to mount protective immune responses against infections, including Mtb, in PLHIV. Identifying highly used and expressed TCR Vβ segments provides insights into mechanisms of host protective immunity in HIV and TB and may offer crucial targets for vaccine development and preventive therapies.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology; Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Brewer, Professor James, Mwandumba, Professor Henry and Garside, Professor Paul
• Date of Award: 2025
• Depositing User: Theses Team
• Unique ID: glathesis:2025-84969
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 27 Mar 2025 15:22
• Last Modified: 27 Mar 2025 15:29
• Thesis DOI: 10.5525/gla.thesis.84969
• URI: https://theses.gla.ac.uk/id/eprint/84969