CTLA4-Ig immunosuppressive activity at the level of dendritic cell/T cell crosstalk

Abstract

Immunosuppressive cytotoxic T lymphocyte associated antigen-4 immunoglobulin fusion proteins (CTLA4-Ig) block the CD28:CD80/86 costimulatory pathway. On a cellular level, CTLA4-Ig is understood to dampen T cell responses. As a mechanism, CTLA4-Ig has been reported to affect dendritic cell (DC) function via inducing the immunosuppressive indoleamine 2,3 dioxygenase (IDO) pathway and promoting a DC regulatory phenotype. We here probed cellular mechanisms of CTLA4-Ig immunoregulation in an allogeneic setting using C57BL/6 splenic or bone marrow derived DCs (BMDCs) as stimulators of allogeneic Balb/c derived T cells. To address whether CTLA4-Ig immunosuppression affected DCs, we pre-exposed C57BL/6 splenic or BMDCs to CTLA4-Ig and removed unbound CTLA4-Ig before co-culture with allogeneic T cells. CTLA4-Ig disappeared rapidly (within 4 h) from the cell membrane by combined internalization and dissociation. These CTLA4-Ig pre-exposed DCs were fully capable of stimulating allogeneic T cell proliferation, suggesting that CTLA4-Ig does not impair the DC stimulatory capacity. Only the presence of CTLA4-Ig during DC/T cell co-culture resulted in the expected inhibition of proliferation. C57BL/6 splenic or BMDCs exposed to CTLA4-Ig did not display IDO activity. We conclude that CTLA4-Ig immunosuppressive activity does not depend on a DC regulatory phenotype but on its presence during DC/T cell interaction.

CTLA4-Ig Preserves Thymus-Derived T Regulatory Cells

“…Consistent with our recent observation (19), using C57BL/6-derived bone marrowYderived dendritic cell (BMDC) as stimulators of allogeneic Balb/c T cells, we first showed that CTLA4-Ig (100 Kg/mL) potently inhibited the allogeneic T-cell proliferative response (Fig. 1A).…”

“…CTLA4-Ig mainly exerts its inhibitory action by interfering with costimulatory signals that are necessary for T-cell activation (19). In addition to that, recent studies report that CTLA4-Ig might further promote inhibition by inducing allospecific deletion by apoptosis (25).…”

“…All assays were performed as described (19). The BMDCs and T cells enriched from Balb/c spleens were generated as previously described (19).…”

IDO expressing dendritic cells suppress allograft rejection of small bowel transplantation in mice by expansion of Foxp3+ regulatory T cells

“…6C). Since cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) expressed by Treg cells could affect DC function via inducing IDO pathway and promoting a DC regulatory phenotype in vivo[35], we suggest that this phenomenon is associated with the existence of newly induced DC with high IDO activity caused by induced Foxp3 + Treg cells. Therefore,the induced Treg cells in turn induced tolerant DC and IDO, composing a loop, maintaining a lasting tolerant state in transplanted mice.…”

Blockade of the Activation of T Cells Around β-Cell by the Targeted CTLA-4 Ig at the Surface of β-Cell

“…cell line, Raji cell was grown in RPMI 1640 supplemented with 10 % FBS. Meanwhile, splenic DCs from BALB/c mice were prepared following previously described protocols [24]. In brief, spleens were injected with type IV collagenase and processed with 400 unit/mL type IV collagenase solution for 30 min at 37°C to prepare single cell suspensions.…”