Tregs in transplantation tolerance: role and therapeutic potential

Abstract

CD4⁺ Foxp3⁺ regulatory T cells (Tregs) are indispensable for preventing autoimmunity, and they play a role in cancer and transplantation settings by restraining immune responses. In this review, we describe evidence for the importance of Tregs in the induction versus maintenance of transplantation tolerance, discussing insights into mechanisms of Treg control of the alloimmune response. Further, we address the therapeutic potential of Tregs as a clinical intervention after transplantation, highlighting engineered CAR-Tregs as well as expansion of donor and host Tregs.

Keywords: Foxp 3; Tregs (regulatory T cells); acute rejection (AR); alloimmunity; tolerance; transplantation.

Figure 1

Mechanisms of Treg suppression. (A) Cell-contact-dependent interactions with T cells. Tregs can mediate suppression via transferring cAMP through gap junctions, membrane bound TGFβ, or the release of cytotoxic Granzyme A and Granzyme B. (B) Cell-contact-dependent interactions with APCs. Tregs express CTLA-4 which outcompetes CD28 on T cells for binding to CD80/CD86 and can mediate trogocytosis of CD80/86 as well as induce DC production of immunosuppressive IDO. LAG-3 binding to MHC-II on APCS inhibits their activation and function, impeding the ability of APCs to activate T cells. (C) Cell-contact-independent environmental perturbations. Tregs secrete immunosuppressive cytokines IL-10, IL-35 and TGFβ. Constitutive expression of the high affinity IL-2 receptor allows Tregs to outcompete T cells for IL-2 acting as a cytokine sink. Tregs increase environmental levels of immunosuppressive adenosine via CD39 and CD73 metabolism of ATP and AMP.

Figure 2

Modulating Treg suppressive ability. (A–C) Interventions that modulate Treg suppressive capacity in transplantation. (A) IL-33 treatment increases inhibitory receptor and CD39/CD73 expression on Tregs. (B) Hypercapnia promotes Treg expansion. (C) Neutralization of Notch-1 signaling increases inhibitory receptor expression and TGFβ production. (D–F) Factors that alter the susceptibility of Tconvs to Treg suppression. (D) Satb1 expression promotes CD25 expression on Tconvs, reducing Tregs’ ability to outcompete Tconvs for IL-2. (E) IL-21 signaling in Tconvs reduces IL-2 production, impairing the ability of Tregs to suppress Tconvs without impeding Tconv survival and function. (F) IL-6 signaling on Tregs can drive a reduction in CD39 expression by Tregs while IL-6 signaling drives Tconv activation and proliferation.