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

Am J Respir Crit Care Med. 2008 Nov 15;178(10):1083-9. doi: 10.1164/rccm.200806-858OC. Epub 2008 Aug 28.


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-gamma-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-gamma 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-gamma-secreting T cells recognizing early secretory antigenic target (ESAT)-6, alpha-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 <or= 0.03). The biggest difference was in the recognition of alpha-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-gamma-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Retroviral Agents / therapeutic use
  • CD4-Positive T-Lymphocytes / immunology*
  • Case-Control Studies
  • Female
  • Forkhead Transcription Factors / immunology*
  • HIV Infections / complications
  • HIV Infections / immunology*
  • Humans
  • Immune Reconstitution Inflammatory Syndrome / immunology*
  • Interferon-gamma / metabolism
  • Longitudinal Studies
  • Male
  • Middle Aged
  • T-Lymphocyte Subsets / immunology
  • Th1 Cells / immunology*
  • Tuberculosis / complications
  • Tuberculosis / immunology*


  • Anti-Retroviral Agents
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interferon-gamma