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


OBJECTIVE
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.


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.
Meintjes
Graeme
G
F.R.C.P., Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa. r.j.wilkinson@imperial.ac.uk.
Wilkinson
Katalin Andrea
KA
Rangaka
Molebogeng Xheeda
MX
Skolimowska
Keira
K
van Veen
Kerryn
K
Abrahams
Musaed
M
Seldon
Ronnett
R
Pepper
Dominique J
DJ
Rebe
Kevin
K
Mouton
Priscilla
P
van Cutsem
Gilles
G
Nicol
Mark Patrick
MP
Maartens
Gary
G
Wilkinson
Robert John
RJ