Figure Legends
Figure 1: Mechanisms of
Treg mediated suppression. Primary Treg suppression mechanisms include
(1) acting as sink for IL-2 due to constitutive high expression of IL-2R
and consequently depriving effector T cells of the crucial cytokine
[121]; (2) secretion of immune-suppressive cytokines IL-10, TGFβ and
IL-35 [122,123]; (3) Granzyme-B dependent killing of target cells
[124]; (4) inhibitory signalling through binding of CTLA-4 on Tregs
and CD80/86 on DCs and reverse signalling via this interaction leading
to elevated levels of IDO in DCs which eventually deplete tryptophan and
starve effector T cells [125, 126]; (5) binding of LAG3 to MHC-II
molecules on DCs causing reduction in Ag presentation [127]; (6)
suppression due to interaction of PD-1 on Tregs and PD-L1 on target
cells [61, 100]; (7) extracellular adenosine generated from ATP in
concert by cell surface CD39 and CD73 (ecto-5’-nucleotidase) interacts
with A2AR on effector T cells and suppresses their function by
increasing cAMP levels [128, 129]; (8) chemokines CCL3 and CCL4
secreted by Tregs bind to CCR5 on effector cells triggering their
migration and subsequent suppression [61, 101].
Figure 2: A
diagrammatic model which highlights the difference in Treg suppression
in healthy and latently infected individuals and active TB subjects in
context of expansion of HLA-DR+CD4+memory T cells. Individuals infected with TB can either clear the
bacteria, become latently infected or come down with active TB disease.
There is also a possibility of reactivation of TB in latently infected
subjects. The reasons for this can be HIV co-infection, treatment with
check-point inhibitors like anti-PD-1, therapies such as anti-TNF for
rheumatoid arthritis etc. HLA-DR+ activated cells are
low in healthy and latently infected individuals and Treg suppression is
good. However, in active TB,
HLA-DR+CD4+ T cells expand and Treg
mediated suppression becomes poor. The Treg suppression pathways that
are rendered inactive in TB are the PD-1/PD-L1 and β-chemokine-CCR5
dependent. The reason for their becoming inactive could be possible
counter-regulation by IL-2, IL-17A, IFNγ, IL-22 that are secreted by the
expanded HLA-DR+CD4+ T cells.
Figure 3: Treg suppression resistant total Teff cells
and Treg suppression sensitive HLA-DR- Teff cells have distinct
expression patterns with respect to certain cytokines and cell surface
receptors. Total Teff and HLA-DR- Teff were sorted by flow cytometry
from 5 pulmonary TB patients. Cells were activated for different times
with anti-CD3/CD28 mitogenic beads, RNA was isolated and an RNA-Seq was
performed. Expression at each time was compared to baseline unactivated
control to arrive at a DEG list. A final DEG list was prepared applying
a cutoff of log2 fold change +/-2.5 and p < 0.05 (for details
on procedure and complete DEG list please see Ahmed A et al., 2018). The
DEG list was further mined to study expression of cytokines, chemokines,
activation markers, cell surface markers and transcription factors. A
summary of these results is shown. The numbers in boxes denote log2 fold
change for expression at 2, 24 and 96 hrs compared to expression at
baseline. For details of the complete DEG list, kindly see [61]