mTOR at the crossroads of T cell proliferation and tolerance

Abstract

Several events control the activation, proliferation, and the continued Ag responsiveness of naïve and memory T lymphocytes. Here we review the individual contributions of TCR, CD28, and IL-2-driven signaling to T cell proliferation and anergy avoidance. The role of mTOR as a rheostat capable of integrating extracellular, plasma membrane-associated, and intracellular signals with relevance to T cell priming and tolerance is discussed.

Figure 1

mTOR relationships in T cells. Arrows are stimulatory interactions, perpendicular lines indicate inhibitory interactions.

Figure 2

The three phases of anergy: induction, implementation/maintenance and reversal. Depicted are the molecules and signaling events critical for the regulation of T cell proliferation and avoidance of unresponsiveness. I) Induction phase. A) Proper activation via the CD3, CD28, and the IL-2R mediates activation and proliferation of the cells and avoidance of anergy. B) Inhibition of CD28 and IL-2R leads to poor mTOR activation, prevents T cell clonal expansion, and favors anergy. C) Proper activation via CD3, CD28, and IL-2R molecules in the presence of mTOR inhibition (Rapamycin) favors anergy, but only slows cell cycle progression. D) Factors shown to promote anergy induction. II) Implementation and maintenance. E) Once anergy is established, intense activation via CD3 and CD28 mAbs promotes T cell proliferation, but fails to activate mTOR and restore antigen responsiveness. F) Shown are molecules associated with the interruption of IL2 expression in anergy (anergy factors). III) Reversal. F) Stimulation of anergic T cells via CD3, CD28, and IL-2R activation activates mTOR and reverses the anergic state. H) Molecular strategies shown sufficient to successfully overcome or reverse established anergy. Proper mTOR signaling is needed to prevent the induction of T cell anergy (A), and to revert the anergic phenotype (G). Likewise deficient mTOR signaling contributes to the maintenance of T cell anergy (E). Crosses, represent blocked signaling. Shading indicates an anergic phenotype.