(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.