Preferential control of induced regulatory T cell homeostasis via a Bim/Bcl-2 axis

Abstract

Apoptosis has an essential role in controlling T cell homeostasis, especially during the contraction phase of an immune response. However, its contribution to the balance between effector and regulatory populations remains unclear. We found that Rag1−/− hosts repopulated with Bim−/− conventional CD4+ T cells (Tconv) resulted in a larger induced regulatory T cell (iTreg) population than mice given wild-type (WT) Tconv. This appears to be due to an increased survival advantage of iTregs compared with activated Tconv in the absence of Bim. Downregulation of Bcl-2 expression and upregulation of Bim expression were more dramatic in WT iTregs than activated Tconv in the absence of IL-2 in vitro. The iTregs generated following Tconv reconstitution of Rag1−/− hosts exhibited lower Bcl-2 expression and higher Bim/Bcl-2 ratio than Tconv, which indicates that iTregs were in an apoptosis-prone state in vivo. A significant proportion of the peripheral iTreg pool exhibits low Bcl-2 expression indicating increased sensitivity to apoptosis, which may be a general characteristic of certain Treg subpopulations. In summary, our data suggest that iTregs and Tconv differ in their sensitivity to apoptotic stimuli due to their altered ratio of Bim/Bcl-2 expression. Modulating the apoptosis pathway may provide novel therapeutic approaches to alter the balance between effector T cells and Tregs.

Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3+ regulatory T cells

“…Accordingly, T reg cell–specific ablation of the intrinsic apoptosis pathway provoked the accumulation of surplus T reg cells. Our approach of systematic assessing pro-survival members of the intrinsic apoptosis pathway revealed that Bcl-2 and Bcl-x L were redundant, in contrast to prior supposition 17,19–21 , while Mcl-1 was essential for T reg cell survival. Furthermore, Mcl-1 appears to represent a rheostat for controlling the T reg cell homeostatic niche, with positive regulation via IL-2 and antagonism by Bim during homeostatic perturbation.…”

“…The leading prosurvival candidate for maintaining T reg cell survival was Bcl-2, because of the dynamic expression of Bcl-2 observed in T reg cells 19–21 and the T reg cell accumulation that occurs in mice with forced Bcl-2 overexpression 21 . However, lethally irradiated mice reconstituted with a 50:50 mixture of C57BL/6.Ly5.1: Bcl2 −/− hematopoietic precursors exhibited a normal proportion of T reg cells derived from the Bcl2 -deficient compartment, demonstrating that Bcl-2 is dispensable for their survival (Fig.…”

“…Several of the proapoptotic BH3-only members of the Bcl-2 family can overcome the prosurvival function of Mcl-1 and thereby initiate apoptosis 30 ; however, elevated numbers of T reg cells have been observed only in Bim-deficient mice 4,17,19,21 . In these mice with germ-line deletion of Bcl2l11 , this effect has been ascribed to additional T cells entering the T reg cell lineage because of defective negative selection 17 , and secondary effects owing to low-grade inflammation 31 .…”

CD4+CD25+Foxp3+IFNγ+ Treg are immunosuppressive in vitro and increase with intensity of the alloresponse in pretransplant MLC

“…In other patients, for reasons unknown, immunosuppressive drugs effectively block iTreg induction which results in disappearance of this subset in the circulation [26][27][28][29]. Whether the balance tips to one side or the other depends on the individual patient's response to the administered immunosuppressive drugs and the cytokine milieu in the microenvironment of cells that are involved in the alloresponse [30][31][32][33]. We speculate that alteration of this balance leading to a reduction of iTreg favors graft rejection.…”

The role of BH3-only proteins in apoptosis within the ovary

“…BIM exists as three major splice variants referred to as BIM S, BIM L and BIM EL (O'Connor et al 1998, Wang et al 2012a. Studies in a number of somatic cell types have shown that BIM, both alone or together with other BH3-only proteins, promotes apoptosis in response to a variety of stimuli including cytokine deprivation, taxol, glucocorticoids, radiation, chemotherapy and endoplasmic reticulum (ER) stressors and has a well-characterised role in the apoptosis of autoreactive thymocytes and B-cells (Bouillet et al 1999, Enders et al 2003, Erlacher et al 2006, Ekoff et al 2007, Happo et al 2010.…”