Dysfunctional bronchoalveolar effector memory CD8+ T cells in tuberculosis-exposed people living with antiretroviral-naïve HIV infection

Maphe Mthembu; Helgard Claassen; Sharon Khuzwayo; Valentin Voillet; Anneta Naidoo; Jule S Spillner; Kennedy Nyamande; Dilshaad Fakey Khan; Priya Maharaj; Mohammed Mitha; Zoey Mhlane; Farina Karim; Erica Andersen-Nissen; Thumbi Ndung'u; Gabriele Pollara; Emily B Wong

doi:10.1016/j.isci.2024.111137

Dysfunctional bronchoalveolar effector memory CD8⁺ T cells in tuberculosis-exposed people living with antiretroviral-naïve HIV infection

iScience. 2024 Oct 16;27(11):111137. doi: 10.1016/j.isci.2024.111137. eCollection 2024 Nov 15.

Authors

Maphe Mthembu^{1

2}, Helgard Claassen^{1

2}, Sharon Khuzwayo^{1

2

3}, Valentin Voillet³, Anneta Naidoo³, Jule S Spillner⁴, Kennedy Nyamande⁵, Dilshaad Fakey Khan⁵, Priya Maharaj⁵, Mohammed Mitha⁵, Zoey Mhlane¹, Farina Karim^{1

2}, Erica Andersen-Nissen³, Thumbi Ndung'u^{1

2

5

6

7}, Gabriele Pollara⁴, Emily B Wong^{1

8}

Affiliations

¹ Africa Health Research Institute, Durban, South Africa.
² University of KwaZulu-Natal, Medical School, Durban, South Africa.
³ Cape Town HVTN Immunology Laboratory, Cape Town, South Africa.
⁴ Division of Infection and Immunity, University London College, London, UK.
⁵ Department of Pulmonology, Inkosi Albert Luthuli Central Hospital, Durban, South Africa.
⁶ HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
⁷ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
⁸ Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.

Abstract

HIV causes susceptibility to respiratory pathogens, including tuberculosis (TB), but the underlying immunological mechanisms remain incompletely understood. We obtained whole blood and bronchoalveolar lavage (BAL) from TB-exposed people in the presence or absence of antiretroviral-naïve HIV co-infection. Bulk transcriptional profiling demonstrated compartment-specific enrichment of immunological processes. Systems-level deconvolution of whole blood from people living with HIV identified elevated type I and type II interferon cytokine activity and T cell proliferation. Transcriptional modules derived from both peripheral blood and sorted BAL immune cells demonstrated an increased frequency of effector memory CD8 T cells in whole BAL samples. Both compartments displayed reduced induction of CD8 T-cell-derived interleukin-17A (IL-17A) in people with HIV, associated with elevated T cell regulatory molecule expression. The data suggest that dysfunctional CD8 T cell responses in uncontrolled HIV may contribute to compromised respiratory immunity to pathogens, a process that could be modulated by host-directed therapies that target CD8 T cell effector functions.

Keywords: Immunology; Virology.