CD86 and CD80 Differentially Modulate the Suppressive Function of Human Regulatory T Cells

Abstract

Regulatory T cells (Treg) are important in maintaining tolerance to self tissues. As both CD28 and CTLA-4 molecules are implicated in the function of Treg, we investigated the ability of their two natural ligands, CD80 and CD86, to influence the Treg-suppressive capacity. During T cell responses to alloantigens expressed on dendritic cells, we observed that Abs against CD86 potently enhanced suppression by CD4+CD25+ Treg. In contrast, blocking CD80 enhanced proliferative responses by impairing Treg suppression. Intriguingly, the relative expression levels of CD80 and CD86 on dendritic cells are modulated during progression from an immature to a mature state, and this correlates with the ability of Treg to suppress responses. Our data show that CD80 and CD86 have opposing functions through CD28 and CTLA-4 on Treg, an observation that has significant implications for manipulation of immune responses and tolerance in vivo.

Proinflammatory mediator–induced reversal of CD4+,CD25+ regulatory T cell–mediated suppression in rheumatoid arthritis

“…This led to a partial abrogation of CD4ϩ,CD25ϩ Treg-mediated suppression in PB and a more profound reversal of suppression in SF cell cultures. This novel finding in RA patients adds to the findings of previous studies on the effects of anti-CD28 mAb on Treg cells in mice and in healthy human controls (21)(22)(23)(24).…”

“…CD28 signaling is important as well, since CD28 -/-mice lack functional CD4ϩ,CD25ϩ Treg cells (20). CD28 might play a dual role though, since strong stimulation through CD28 via high levels of CD86 on dendritic cells or via anti-CD28 monoclonal antibody (mAb) can lead to abrogation of CD4ϩ,CD25ϩ Treg-mediated suppression in mice and healthy humans (21)(22)(23)(24).…”

HIV-Specific IL-10-Positive CD8+ T Cells Suppress Cytolysis and IL-2 Production by CD8+ T Cells

“…We postulate that this suppression is mediated by similar mechanisms that were described previously in other non-HIV regulatory T cell populations. Suppression may occur through direct binding of inhibitory cell surface molecules such as CTLA-4 to costimulatory molecules (including CD80 and CD86) on effector T cells (43,44). These HIV-specific suppressor CD8 ϩ T cells may also recognize MHC peptide complexes on the cell surface of APCs, triggering the up-regulation of the inhibitory receptors Iglike transcripts (ILT)3 and ILT4 and the down-regulation of costimulatory molecules rendering the APC tolerogenic (33,45,46).…”

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

“…As both CD28 and CTLA-4 molecules are implicated in the function of T R cells, we investigated the ability of their two natural ligands B7.1 (CD80) and B7.2 (CD86) to influence the T R -suppressive capacity [37]. The relative expression levels of B7.1 and B7.2 on DC is modulated by T R cells during progression from an immature to a mature state, and this correlates with the ability of T R cells to suppress responses [27,38].…”