Type 1 helper T cells and FoxP3-positive T cells in HIV-tuberculosis- associated immune reconstitution inflammatory syndrome

Graeme Meintjes, Katalin Andrea Wilkinson, Molebogeng Xheeda Rangaka, Keira Skolimowska, Kerryn Van Veen, Musaed Abrahams, Ronnett Seldon, Dominique J. Pepper, Kevin Rebe, Priscilla Mouton, Gilles Van Cutsem, Mark Patrick Nicol, Gary Maartens, Robert John Wilkinson

Research output: Contribution to journalArticlepeer-review

121 Citations (Scopus)


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-γ-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-γ 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-γ- secreting T cells recognizing early secretory antigenic target (ESAT)-6, α-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 α-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-γ-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.

Original languageEnglish
Pages (from-to)1083-1089
Number of pages7
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number10
Publication statusPublished - 15 Nov 2008
Externally publishedYes


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