Protection from graft-versus-host disease by HIV-1 envelope protein gp120-mediated activation of human CD4+CD25+ regulatory T cells

Abstract

Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) represent a unique T-cell lineage that is endowed with the ability to actively suppress immune responses. Therefore, approaches to modulate Treg function in vivo could provide ways to enhance or reduce immune responses and lead to novel therapies. Here we show that the CD4 binding human immunodeficiency virus-1 envelope glycoprotein gp120 is a useful and potent tool for functional activation of human Tregs in vitro and in vivo. Gp120 activates human Tregs by binding and signaling through CD4. Upon stimulation with gp120, human Tregs accumulate cyclic adenosine monophosphate (cAMP) in their cytosol. Inhibition of endogeneous cAMP synthesis prevents gp120-mediated Treg activation. Employing a xenogeneic graft versus host disease model that has been shown to be applicable for the functional analysis of human Tregs in vivo, we further show that a single dose of gp120 is sufficient to prevent lethal graft versus host disease and that the tolerizing effect of gp120 is strictly dependent on the presence of human Tregs and their up-regulation of cAMP upon gp120-mediated activation. Our findings demonstrate that stimulation via the CD4 receptor represents a T-cell receptor-independent Treg activating pathway with potential to induce immunologic tolerance in vivo.

Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3 + regulatory T cells

“…Human T-cell subsets (29,51) and murine CD4 + CD25 + nTreg and CD4 + CD25 − Tconv (26) were isolated and stimulated as before. Details can be found in SI Materials and Methods.…”

Interferon-α Suppresses cAMP to Disarm Human Regulatory T Cells

“…In some experiments, cAMP production was repressed in Treg by pretreatment with the adenylate cyclase inhibitor MDL-12 (Calbiochem; ref. 15). …”

“…Development of xenogeneic GvHD was characterized by decelerated growth and weight loss and was accompanied by massive inflammatory infiltration of human T cells into all murine organs (15). Cotransfer of resting human Treg at a 4:1 ratio (PBMC/Treg) decelerated GvHD onset and increased the median time to death by 10 days (range, 5-15 days) (15). Untreated mice served as controls.…”

Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1)

“…The inhibition of Il2 gene expression in effector CD4 + T cells is a characteristic feature of nTreg-mediated suppression (2). nTreg cells harbor high levels of cAMP (3), and the contactdependent transfer of cAMP from nTregs to effector CD4 + T cells was shown to contribute to nTreg-mediated suppression of effector CD4 + T cells (4,5). Inhibition of cAMP degradation by the phosphodiesterase (PDE)-4 inhibitor rolipram enhanced nTreg-mediated suppression of effector CD4 + T cells both in vitro and in vivo (6).…”