The observed (p=0.0019, Fig 5A) and a positive

The frequency of CD4+CD25+Foxp3+
T-cells(Tregs) increased almost 6 times more in APTBs than in HCs and 2.6 times
more than in LTBIs.  To get an insight of the subset conversion
among CD4+ cells in M.tb infected individuals, we determined the
mean ratios of CD4+ cells to Tregs. A significant differences
in the ratios of CD4+ to CD4+CD25+
(p<0.0001, Fig. 3A), CD4+CD25+Foxp3+ (p<0.0001, Fig. 3B) and CD4+Foxp3+ (p<0.0001, Fig. 3C) was observed among the groups (Table 2). A trend of decreased ratio of CD4+ cells to CD4+CD25+Foxp3+ from HCs to LTBIs and to APTBs was observed (Fig. 3B)   Impact of bacillary load on frequencies of CD4+and Tregs was not observed in APTBs (p>0.05, Fig 4A-4E). In the study cohort a significant
negative correlation between BMI and Tregs was observed (p=0.0019, Fig 5A) and
a positive correlation between CD4+ cells and BMI was observed
though it was not significant (p>0.05, Fig 5A). Also no correlation of Tregs
with age and sex was observed for the same (p>0.05 for both). (Fig 5B, 5C)


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    In the present study, a trend of decreased
ratio of total CD4+ T-cells to Tregs phenotype from the controls to
the latently infected individuals and active pulmonary tuberculosis patients
along with significantly negative correlation between CD4+CD25-Foxp3-
and   CD4+CD25+Foxp3+
T-cells indicate that  CD4+ T-cell is not
a stable phenotype and may convert to regulatory T-cells in chronic M.tb
infection. The development of active tuberculosis may be attributed to the
enhance inhibition of immune response by  these regulatory T-cell sub-sets.

Sub-set conversion
for all known T-helper cell subsets in chronic inflammation has been reported
and most of the studies were for Th17
cells. Factors determining such cellular plasticity of
effector CD4+ T
cell remain poorly understood.
Recent reports suggested that such heterogeneity and plasticity is attributed to collaboration and cross-regulation
between various essential cytokines and transcription factors during the
process of T-helper cell differentiation. 7
It has been reported that, IL-6 or
IL-1 receptor signaling and subsequent STAT3 activation can convert T-reg cells
to Th17 cells and TH17 cell can switch to T-reg cells under influence of IL-12
signaling and subsequent STAT4 activity.8,9,10

et al  in a case control study using flow
cytometry  and confocal microscopy  of asthma patients  observed upregulation of multiple
transcription factors T-bet,GATA-3, RORy and Foxp3 and in some cell sub types
,upto four transcription factors were co-expressed  upon stimulation and display plasticity.11

Alexander SA et al
using in-vivo model of human –into mouse xenogeneic graft-versus –host disease
determined that PD- L1 converted TBET+ TH1 cells into
FOXP3+ regulatory T (Treg) cells in vivo, thereby
preventing human-into-mouse xenogeneic GVHD (xGVHD). He also demonstrated that
PD1-PD-L1 pathway through SHP1/SHP2 signaling pathway  plays a special role in modulation of T-helper
cells plasticity  resulting in T-reg
phenotype that severally impaired cell mediated immunity. 12

Asano T et al
observed that PD1 regulates IL-2 induced Tregs proliferation and prolong Tregs
survival in murine models and in patients receiving low –IL-2 therapy.13