Chronic phase: novel qualitative studies of Treg function
in humans highlight emergence of Treg resistant T effectors in chronic
TB.
In contrast to the many studies that have probed Treg frequency, few
human or animal model studies have analyzed qualitative aspects of Treg
function in TB. Some studies have shown that Treg cells from pulmonary
TB patients retain their capacity to suppress autologous Teff cells
[83-85]. However, data from our laboratory shows that autologous
suppression mediated by
CD4+CD45RA-CD25+CD127lomemory Treg cells isolated from subjects with pulmonary TB in south
India is significantly compromised [61]. By testing isolated Tregs
from healthy controls on Teff isolated from TB subjects and vice versa,
we demonstrated this impairment is not due to the loss of suppressive
potential of Treg cells isolated from TB subjects; instead it is due to
the effector cells from TB subjects acquiring resistance to Treg
mediated suppression [61]. Thus,
CD127loCD25+ Treg cells from TB
subjects were effective in suppressing Teff from healthy controls but
not those from TB subjects; conversely, Treg isolated from healthy
controls effectively suppressed autologous Teff but failed to suppress
Teff from TB subjects [61]. Phenotypic analysis of the Treg
resistant Teff isolated from TB subjects highlighted the presence of a
significant proportion of highly activated cells that expressed HLA-DR
and CD38; depletion of the HLA-DR+ subset in
particular, restored sensitivity of HLA-DR- Teff to autologous Treg
suppression, thereby confirming that resistance of Teff from TB subjects
to Treg mediated suppression was due to the presence of
HLA-DR+ cells [61]. The expansion of
HLA-DR+CD4+ T cells in TB is driven
by infection as anti-tubercular (anti-TB) treatment reduced the
frequencies of HLA-DR+CD4+ T cells
[61, 86, 87]; indeed we have shown that anti-TB treatment by
dampening the frequency of HLA-DR+ cells restores T
effector cell sensitivity to autologous Treg cell mediated suppression
[61]. Consequently, measuring
HLA-DR+CD4+ T cell frequency can
potentially be used to monitor treatment responses and predict efficacy
of treatment [87]. In this context, our observation that
HLA-DR+CD4+ T effectors isolated
from subjects with pulmonary TB become resistant to Treg mediated
suppression provides a mechanistic basis for how the expansion of
HLA-DR+ T effectors may be detrimental in TB (Figure
2, 61).
The observations of the emergence of Treg resistant Teff in TB is
consistent with data from other chronic inflammatory conditions,
particularly, autoimmune disorders (Table 2).
CD161+Th17 cells enriched in the synovial fluid of
rheumatoid arthritis patients are resistant to Treg mediated suppression
and their depletion restores suppression in in vitro cultures
[65]. A similar phenomenon of the emergence of suppression resistant
effectors has been reported in systemic lupus erythromatosis [88],
multiple sclerosis [89], type-1 diabetes [63, 90] and juvenile
idiopathic arthritis [91], with potentially varying mechanisms
underpinning such resistance. In multiple sclerosis, it was attributed
to high Teff cell derived granzyme B [89]; in type-1 diabetes due to
downregulation of TGFβRII on Teff cells and consequently reduced TGFβ
mediated suppression [90] and in juvenile idiopathic arthritis, like
TB, due to expansion of activated
CD69+HLA-DR+ Teff cells which were
Treg suppression resistant [91].