(III) Signal strength
A third potentially important consideration in the mechanisms that underpin how activated, HLA-DR+ T effectors become resistant to Treg cells may be linked to the quality and strength of the primary signal that activates effector cells. The strength of activating signal shapes the nature of the immune response, with high signal strength leading to Th1 and low signal strength to Th2, Tfh and memory T cell differentiation [reviewed in 112, 113]. Previous studies show that effectors activated by a very strong signal strength become refractory to suppression mediated by Treg cells- co-culture of human CD25- Teff and autologous CD25+ Treg resulted in suppression only when stimulated with soluble anti-CD3 (weak TCR signal) and not when activated with plate-bound anti-CD3 (strong TCR signal) [114]. Whether this is pertinent in the context of TB remains to be tested. What has been demonstrated from mouse studies is that persistently activated CD4 T cells specific for the secretory Mtb antigen ESAT6, which is expressed in abundance throughout infection, fail to confer protection, whereas, CD4+ T cells specific for an Mtb antigen that has more controlled expression, e.g. Ag85B, can confer protection greater protection [115]. The failure of ESAT6 specific cells to confer protection was linked to the fact that these cells are more exhausted and terminally differentiated; i.e. express higher KLRG1, lower CCR7, CD127 and CD62L; compared to Ag85B specific cells [115]. Whether Treg resistant HLA-DR+ Teff cells isolated from TB subjects arise due to persistent antigen stimulation and bear markers of exhaustion remains to be confirmed.