Phenotypical and functional specialization of FOXP3+ regulatory T cells

Abstract

Forkhead box P3 (FOXP3)(+) regulatory T (T(Reg)) cells prevent autoimmune disease, maintain immune homeostasis and modulate immune responses during infection. To accomplish these tasks, T(Reg) cell activity is precisely controlled, and this requires T(Reg) cells to alter their migratory, functional and homeostatic properties in response to specific cues in the immune environment. We review progress in understanding the diversity of T(Reg) cells, T(Reg) cell function in different anatomical and inflammatory settings, and the influence of the immune environment on T(Reg) cell activity. We also consider how these factors affect immune-mediated disease in the contexts of infection, autoimmunity, cancer and transplantation.

Figure 1. Differing immunosuppressive mechanisms used by T_Reg cells in lymphoid vs. non-lymphoid tissues

(Left) T_Reg cells in secondary lymphoid tissues use multiple mechanisms to inhibit DC function and block initiation of autoimmunity or prevent tumor clearance. (Right) T_Reg cell production of IL-10 is essential for immunoregulation at mucosal tissues such as the intestines, lungs and skin. The relative importance of other immunosuppressive mechanisms used by T_Reg cells (shown in white box) in lymphoid vs. non-lymphoid tissues remains to be established

Figure 2. Functional Differentiation of T_reg cells and T_conv cells

The differentiation of naive T_H cells into functionally distinct effector subsets (T_H17, T_H1, T_H2, induced T_R) is dependent on the induction of key transcriptional regulators (RORγT, T-bet, GATA3, Foxp3) following TCR stimulation in conjunction with cytokine signaling/STAT activation. Comparably, thymic-derived T_reg cells utilize specific molecular programs driven by STAT3, T-bet, or IRF4 to restrain particular types of immune responses orchestrated by distinct effector T cell subsets.

Figure 3. Modulation of T_Reg cell activity can be by different factors in the immune environment

(Left) The vitamin-A metabolite retinoic acid (RA) can boost T_Reg cell activity within the intestine by inducing Foxp3 expression in naïve T cells and directing the expression of gut-homing receptors on both T_Reg and iT_Reg cells. (Right) During T_H17-driven inflammation, IL-6 impairs T_Reg cell activity both by directly blocking T_Reg function as well as by promoting T_H17 differentiation at the expense of iT_Reg generation. (Middle) During type-1 inflammatory responses, such as Mtb infection, IFNγ and IL-12 direct T_H1 differentiation. Coordinately, IFNγ produced in response to infection directs the differentiation of T-bet⁺ T_Reg cells that are specialized to restrain pro-inflammatory T_H1 cells.