Phenotypic Profile of Mycobacterium tuberculosis-Specific CD4 T-Cell Responses in People With Advanced Human Immunodeficiency Virus Who Develop Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

Raymond M Moseki; Daniel L Barber; Elsa Du Bruyn; Muki Shey; Helen Van der Plas; Robert J Wilkinson; Graeme Meintjes; Catherine Riou

doi:10.1093/ofid/ofac546

Phenotypic Profile of Mycobacterium tuberculosis-Specific CD4 T-Cell Responses in People With Advanced Human Immunodeficiency Virus Who Develop Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

Open Forum Infect Dis. 2022 Oct 17;10(1):ofac546. doi: 10.1093/ofid/ofac546. eCollection 2023 Jan.

Authors

Raymond M Moseki^{1

2}, Daniel L Barber³, Elsa Du Bruyn^{1

2}, Muki Shey^{1

4}, Helen Van der Plas^{2

4}, Robert J Wilkinson^{1

2

4

5

6}, Graeme Meintjes^{1

2

4}, Catherine Riou^{1

2

7}

Affiliations

¹ Wellcome Center for Infectious Diseases Research in Africa (CIDRI-Africa), University of Cape Town, Cape Town, South Africa.
² Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa.
³ T Lymphocyte Biology Section, Laboratory of Parasitic Diseases, National Institute of Health, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
⁴ Department of Medicine, University of Cape Town, Cape Town, South Africa.
⁵ Department of Infectious Diseases, Imperial College London, London, United Kingdom.
⁶ The Francis Crick Institute, London, United Kingdom.
⁷ Department of Pathology, Division of Medical Virology, University of Cape Town, Cape Town, South Africa.

Abstract

Background: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of cotreatment for TB and human immunodeficiency virus (HIV)-1. We characterized Mycobacterium tuberculosis (Mtb)-specific CD4 T-cell phenotype and transcription factor profile associated with the development of TB-IRIS.

Methods: We examined the role of CD4 T-cell transcription factors in a murine model of mycobacterial IRIS. In humans, we used a longitudinal study design to compare the magnitude of antiretroviral therapy, activation, transcription factor profile, and cytotoxic potential of Mtb-specific CD4 T cells between TB-IRIS (n = 25) and appropriate non-IRIS control patients (n = 18) using flow cytometry.

Results: In the murine model, CD4 T-cell expression of Eomesodermin (Eomes), but not Tbet, was associated with experimentally induced IRIS. In patients, TB-IRIS onset was associated with the expansion of Mtb-specific IFNγ⁺CD4 T cells (P = .039). Patients with TB-IRIS had higher HLA-DR expression (P = .016), but no differences in the expression of T-bet or Eomes were observed. At TB-IRIS onset, Eomes⁺Tbet⁺Mtb-specific IFNγ⁺CD4⁺ T cells showed higher expression of granzyme B in patients with TB-IRIS (P = .026).

Conclusions: Although the murine model of Mycobacterium avium complex-IRIS suggests that Eomes⁺CD4 T cells underly IRIS, TB-IRIS was not associated with Eomes expression in patients. Mycobacterium tuberculosis-specific IFNγ⁺CD4 T-cell responses in TB-IRIS patients are differentiated, highly activated, and potentially cytotoxic.

Keywords: HIV-1/TB coinfection; Tbet/Eomes; Th-1 responses; immune activation; paradoxical TB-IRIS.

Abstract

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