Regulatory T cells: a brief introduction
Extensive experimental evidence shows that it is not only important to
mount an effective immune response but equally crucial to efficiently
control it. A vital cog in the immune regulation machinery is a class of
CD4+ T cells, termed as regulatory T cells or Treg
cells. Treg cells have been extensively studied particularly in
autoimmune disorders, as potential therapeutic targets. Tregs can be
broadly classified as (a) thymic or tTregs/natural or nTregs, which
originate in the thymus and, (b) induced or iTregs/peripheral or pTregs,
which develop in the periphery during T cell activation. Development of
nTregs is influenced by signal strength [1,2] co-stimulatory CD28
signaling, ICOS/ICOSL interactions, and thymic stromal lymphoprotein
(TSLP) [3-5]. Transcription factor FoxP3 is a key regulator of Treg
development, maintenance and suppressive function [6-10] and its
expression in
CD4+CD25hiFoxP3+tTregs is positively regulated by IL-2 [11], transcription factors
NFAT, STAT5 and Smad3 [12-14] and negatively regulated by PI3K, Akt
and mTOR [15]. However, FoxP3 expression can also be induced upon
exposure to non-self antigens in
CD4+FoxP3- conventional T cells,
which then differentiate into FoxP3+ Tregs known as
pTregs/iTregs by a process regulated by cytokines TGF- β and
IL-2 [16,17], suboptimal CD28 mediated co-stimulation [18], and
sub-optimal TCR triggering [19, 20]. While nTregs maintain tolerance
and homeostasis systemically, pTreg/iTregs are crucial for dampening
over-exuberant antigen specific immune responses locally [21].
Inducible T regulatory type 1 or Tr1 cells, a sub-class of
pTregs/iTregs, mediate suppressive effects via the immune-regulatory
cytokine IL-10 [22]; cell surface markers CD49b and LAG3 promote Tr1
differentiation [23]; and IL-27, IL-6, IL-21, IL-10, immature DCs
and plasmacytoid DCs promote Tr1 expansion [24-28]. nTreg
suppression mechanisms can be contact-dependent or -independent (Figure
1). A breakdown in Treg suppression can occur due to (i) reduction in
Treg frequencies, (ii) loss of Treg immunosuppressive capacity or due to
(iii) resistance acquired by effector T cells (Teff) to Treg mediated
suppression, with impact on a variety of clinical conditions (Table 1
and 2). This review focuses on how these mechanisms may contribute to
disease in the context of tuberculosis (TB).