Induction of T cell anergy: integration of environmental cues and infectious tolerance

Abstract

Anergy is a state of long-term hyporesponsiveness in T cells that is characterized by an active repression of TCR signaling and IL-2 expression [1]. Several forms of anergy have been described and the past few years have brought to light an increasing number of 'anergic factors' involved in the induction and the active maintenance of the state in lymphocytes. The role of mTOR and other related metabolic sensors and regulators has recently emerged as of particular importance in broadening our view of anergy-inducing signals. We will discuss the role of these molecules in regulating the choice between anergy and activation, a decision faced by all T cells undergoing TCR stimulation. We will then explore the relationship between the induction of anergy and the induction of regulatory T cells as well as the potential crosstalk responsible for the phenomenon of infectious tolerance.

Figure 1. Extending the signal 2 paradigm

induction of anergy in T cells was initially described as the result of TCR (signal 1) without concomitant CD28 and IL-2R signaling (signal 2). Recent studies have further demonstrated that the T cell actively sense its microenvironment, through mTOR dependent and independent mechanisms, for available energy and nutrients, as well as additional negative cues such as adenosine. This regulates the T cell commitment to switch its metabolic machinery and enter the S phase of the cell cycle. Interestingly, failing to positively commit to full T cell activation in such cases induces anergy and long-term tolerance in the T cell. Full lines represent active pathways and dashed lines represent blunted pathways during the induction of T cell anergy in an anergic environment.

Figure 2. Infectious tolerance by creating an “anergy-inducing” environment

It has recently been shown that Tregs can influence the microenvironment in which a naïve T cell gets activated. First, Tregs can, via CTLA-4 expression and IL-10 and TGF-β secretion, induce various amino acid-consuming enzymes, as well as down-regulate CD80 and CD86 expression, in DCs. Second, Tregs, via their constitutive expression of the high affinity chain of the IL2R (CD25), can actively consume IL-2 in the extracellular milieu. Finally, Tregs express the 5′-ectonucleotidase CD73 and the ATPase/ADPase CD39 and activated Tregs have the potency to hydrolyze extracellular ATP into adenosine, thus favoring an hypoxic environment. Full lines represent active pathways and dashed lines represent blunted pathways during active suppression of naïve T cell activation by Tregs.