Question

 

1. Describe two mechanisms by which regulatory T cells can prevent helper T cells from becoming activated.

2. Summarize the pros and cons of “live” (attenuated) vs. “killed” (inactivated) vaccines.

Answer 1

2.1. The mechanisms of Treg action remain poorly understood and contentious. Differences between in vitro and in vivo requirements, particularly with regard to the inhibitory cytokines IL-10 and TGF-β, have fuelled the controversy. Many of the discrepancies may arise because, unlike the controlled environment of in vitro suppression, in any given in vivo model the stage of activation or anatomical location of successful target T-cell–Treg interactions has been poorly defined. The latest identification of new (and revamped) inhibitory mechanisms may bridge the in vitro and in vivo divide. As recently reviewed,66suppressive mechanisms can be divided into three categories: cell–cell contact, local secretion of inhibitory cytokines and local competition for growth factors (Fig. 2). In each category there are multiple examples of inhibitory pathways that are probably not mutually exclusive.

Figure 2

Mechanisms of regulatory T-cell (Treg) suppression. (a) Cell–cell contact. Tregs may suppress target cells via direct interaction of receptor–ligand pairs on Tregs and target cells; delivery of suppressive factors via gap junctions including cyclic adenosine monophosphate (cAMP); direct cytolysis; membrane-bound suppressive cytokines such as transforming growth factor-β (TGF-β); and/or indirectly via modulating the antigen-presenting cell (APC) through cell–cell contact, possibly through reverse signalling via Treg–cytotoxic T-lymphocyte antigen-4 (CTLA-4) engagement of B7 on dendritic cells. (b) Soluble suppressive factors. Tregs can directly secrete interleukin-10 (IL-10), TGF-β and IL-35 or induce APCs to secrete such factors. Expression of CD73/CD39 by Tregs facilitates the local generation of adenosine that can down-modulate immune function. (c) Competition. Tregs may compete for some cytokines that signal via receptors that contain the common γ-chain (IL-2, IL-4 and IL-7). Additionally they may compete for APC costimulation via constitutive expression of CTLA-4. Red arrow indicates an inhibitory signal.