Regulatory T-cell homeostasis: steady-state maintenance and modulation during inflammation

Abstract

Regulatory T (Treg) cells play a vital role in the prevention of autoimmunity and the maintenance of self-tolerance, but these cells also have an active role in inhibiting immune responses during viral, bacterial, and parasitic infections. Although excessive Treg activity can lead to immunodeficiency, chronic infection, and cancer, too little Treg activity results in autoimmunity and immunopathology and impairs the quality of pathogen-specific responses. Recent studies have helped define the homeostatic mechanisms that support the diverse pool of peripheral Treg cells under steady-state conditions and delineate how the abundance and function of Treg cells changes during inflammation. These findings are highly relevant for developing effective strategies to manipulate Treg cell activity to promote allograft tolerance and treat autoimmunity, chronic infection, and cancer.

Keywords: autoimmunity; homeostasis; inflammation; regulatory T cells.

Figure 1. DC-driven Treg cell expansion is CD28-dependent

Total number (left) and frequency (right) of Foxp3+ Treg cells in the spleens of wild-type and Cd28^−/− mice treated with B16.Flt3L tumors for two weeks or with IL-2 immune complexes for 7 days as indicated.

Figure 2. Separate homeostatic pathways for different Treg cell populations

(Left) Paracrine IL-2 maintains quiescent CD44loCCR7hi ‘central’ Treg cells in secondary lymphoid tissues by induction of pro-survival factors such as Mcl-1. (Right) ‘Effector’ Treg cells in non-lymphoid tissues balance rapid proliferation and cell death, and this balance depends in part TCR/co-stimulatory receptor signaling.

Figure 3. CD18 is not required for Treg cell access to IL-2 in secondary lymphoid tissues

CD4⁺CD25⁺ Treg cells were isolated from WT and Itgb2−/− (CD18-knockout) mice and adoptively transferred into congenically marked WT recipient mice. At 36 hours after transfer, pStat5 staining was performed directly ex vivo to determine the ability of endogenous Treg cells (left), recovered WT Treg cells (middle) and recovered Itgb2^−/− Treg cells (right) to access paracrine IL-2 in the spleen. The average pStat5⁺ frequencies for these Treg cell populations are shown in the bar graph at the far right (n=3 data points per group). The CD18 integrin constitutes the beta subunit of LFA-1 (when paired with CD11a). Whereas LFA-1-dependent cellular synapses were shown to facilitate IL-2 signaling in effector T cells (see reference, these data suggest that Treg cells utilize a mechanism distinct from LFA-1 integrin interactions to access paracrine IL-2 in the T cell zones of the spleen.

Figure 4

Control of Treg cell activity is critical for proper resolution of inflammation.