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]