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).