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].