Protection from graft-versus-host disease by HIV-1 envelope protein gp120-mediated activation of human CD4+CD25+ regulatory T cells.
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.
Department of Dermatology, Johannes Gutenberg-University, Mainz, Germany. christian.becker@hautklinik.klinik.uni-mainz.de
Christian
C
Becker
Christian
C
Taube
Tobias
T
Bopp
Christoph
C
Becker
Kai
K
Michel
Jan
J
Kubach
Sebastian
S
Reuter
Nina
N
Dehzad
Markus F
MF
Neurath
Kurt
K
Reifenberg
Franz-Joseph
FJ
Schneider
Edgar
E
Schmitt
Helmut
H
Jonuleit
D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000276:immunology; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000494:pharmacology*; D015497:HIV-1; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014183:Transplantation, Heterologous
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1; D000242:Cyclic AMP