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Type 1 Helper T Cells and FoxP3-positive T Cells in HIV–Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome

¹ Institute of Infectious Diseases and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa; ² GF Jooste Hospital, Manenberg, South Africa; ³ National Institute for Medical Research, London, United Kingdom; ⁴ Division of Medicine, Imperial College London, London, United Kingdom; ⁵ Provincial Administration of the Western Cape, Khayelitsha, South Africa; ⁶ Médicins sans Frontiéres, Khayelitsha, South Africa; and ⁷ Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa

Correspondence and requests for reprints should be addressed to Robert J. Wilkinson, F.R.C.P., Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa. E-mail: r.j.wilkinson{at}imperial.ac.uk

Rationale: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB–IRIS) induced by combination antiretroviral therapy (cART) has been attributed to dysregulated expansion of tuberculin PPD–specific IFN-–secreting CD4⁺ T cells.

Objectives: To investigate the role of type 1 helper T cell expansions and regulatory T cells in HIV–TB IRIS.

Methods: Longitudinal and cross-sectional studies of Mycobacterium tuberculosis–specific IFN- enzyme-linked immunospot responses and flow cytometric analysis of blood cells from a total of 129 adults with HIV-1–associated tuberculosis, 98 of whom were prescribed cART.

Measurements and Main Results: In cross-sectional analysis the frequency of IFN-–secreting T cells recognizing early secretory antigenic target (ESAT)-6, -crystallins 1 and 2, and PPD of M. tuberculosis was higher in patients with TB–IRIS than in similar patients treated for both HIV-1 and tuberculosis who did not develop IRIS (non-IRIS; P 0.03). The biggest difference was in the recognition of -crystallin molecules: peptide mapping indicated a polyclonal response. Flow cytometric analysis indicated equal proportions of CD4⁺ and CD8⁺ cells positive for activation markers HLA-DR and CD71 in both patients with TB–IRIS and non-IRIS patients. The percentage of CD4⁺ cells positive for FoxP3 (Forkhead box P3) was low in both groups (TB–IRIS, 5.3 ± 4.5; non-IRIS, 2.46 ± 2.46; P = 0.13). Eight weeks of longitudinal analysis of patients with tuberculosis who were starting cART showed dynamic changes in antigen-specific IFN-–secreting T cells in both the TB–IRIS and non-IRIS groups: the only significant trend was an increased response to PPD in the TB–IRIS group (P = 0.041).

Conclusions: There is an association between helper T-cell type 1 expansions and TB–IRIS, but the occurrence of similar expansions in non-IRIS brings into question whether these are causal. The defect in immune regulation responsible for TB–IRIS remains to be fully elucidated.

Key Words: tuberculosis • HIV • immune reconstitution inflammatory syndrome • FoxP3 • type 1 helper T cells

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Little is known of the pathogenesis of the HIV–TB immune reconstitution inflammatory syndrome (TB–IRIS), although preliminary analyses have attributed it to dysregulated helper T-cell type 1 (Th1) expansion. What This Study Adds to the Field Dynamic Mycobacterium tuberculosis–specific Th1 responses associate with TB–IRIS, although the presence of such responses in patients who did not develop the syndrome suggests that other regulatory factors are involved.

 

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