16 research outputs found
Linking Two Immuno-Suppressive Molecules: Indoleamine 2,3 Dioxygenase Can Modify HLA-G Cell-Surface Expression1
Nonclassical human leukocyte antigen (HLA) class I molecule
HLA-G and indoleamine 2,3 dioxygenase (INDO) in humans and
mice, respectively, have been shown to play crucial immunosuppressive
roles in fetal-maternal tolerance. HLA-G inhibits
natural killer and T cell function by high-affinity interaction with
inhibitory receptors, and INDO acts by depleting the surrounding
microenvironment of the essential amino acid tryptophan,
thus inhibiting T cell proliferation. We investigated whether
HLA-G expression and INDO function were linked. Working
with antigen-presenting cell (APC) lines and monocytes, we
found that functional inhibition of INDO by 1-methyl-tryptophan
induced cell surface expression of HLA-G1 by HLA-G1-
negative APCs that were originally cell-surface negative, and
that in reverse, the functional boost of INDO by high concentrations
of tryptophan induced a complete loss of HLA-G1 cell
surface expression by APCs that were originally cell-surface
HLA-G1-positive. This mechanism was shown to be posttranslational
because HLA-G protein cell contents remained unaffected
by the treatments used. Furthermore, HLA-G cell surface
expression regulation by INDO seems to relate to INDO function,
but not to tryptophan catabolism itself. Potentia
Tolerogenic Function of Dimeric Forms of HLA-G Recombinant Proteins: A Comparative Study In Vivo
HLA-G is a natural tolerogenic molecule involved in the best example of tolerance to foreign tissues there is: the maternal-fetal tolerance. The further involvement of HLA-G in the tolerance of allogeneic transplants has also been demonstrated and some of its mechanisms of action have been elucidated. For these reasons, therapeutic HLA-G molecules for tolerance induction in transplantation are actively investigated. In the present study, we studied the tolerogenic functions of three different HLA-G recombinant proteins: HLA-G heavy chain fused to β2-microglobulin (B2M), HLA-G heavy chain fused to B2M and to the Fc portion of an immunoglobulin, and HLA-G alpha-1 domain either fused to the Fc part of an immunoglobulin or as a synthetic peptide. Our results demonstrate the tolerogenic function of B2M-HLA-G fusion proteins, and especially of B2M-HLA-G5, which were capable of significantly delaying allogeneic skin graft rejection in a murine in vivo transplantation model. The results from our studies suggest that HLA-G recombinant proteins are relevant candidates for tolerance induction in human transplantation
Multimeric structures of HLA-G isoforms function through differential binding to LILRB receptors
The non-classical Human leukocyte antigen G (HLA-G) differs from classical HLA class I molecules by its low genetic diversity, a tissue-restricted expression, the existence of seven isoforms, and immuno-inhibitory functions. Most of the known functions of HLA-G concern the membrane-bound HLA-G1 and soluble HLA-G5 isoforms, which present the typical structure of classical HLA class I molecule: a heavy chain of three globular domains α(1)-α(2)-α(3) non-covalently bound to β-2-microglobulin (B2M) and a peptide. Very little is known of the structural features and functions of other HLA-G isoforms or structural conformations other than B2M-associated HLA-G1 and HLA-G5. In the present work, we studied the capability of all isoforms to form homomultimers, and investigated whether they could bind to, and function through, the known HLA-G receptors LILRB1 and LILRB2. We report that all HLA-G isoforms may form homodimers, demonstrating for the first time the existence of HLA-G4 dimers. We also report that the HLA-G α(1)-α(3) structure, which constitutes the extracellular part of HLA-G2 and HLA-G6, binds the LILRB2 receptor but not LILRB1. This is the first report of a receptor for a truncated HLA-G isoform. Following up on this finding, we show that the α(1)-α(3)-Fc structure coated on agarose beads is tolerogenic and capable of prolonging the survival of skin allografts in B6-mice and in a LILRB2-transgenic mouse model. This study is the first proof of concept that truncated HLA-G isoforms could be used as therapeutic agents
Transferts trogocytiques de fonctions et sensibilités (un mécanisme de régulation immunitaire par mimétisme démontré dans le cas de la molécule tolérogène HLA-G)
PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF
Proper Regrafting of Ig-Like Transcript 2 after Trogocytosis Allows a Functional Cell–Cell Transfer of Sensitivity
Linking Two Immuno-Suppressive Molecules: Indoleamine 2,3 Dioxygenase Can Modify HLA-G Cell-Surface Expression 1
ABSTRAC
ILT2-mediated signaling by B2M-HLA-G5 and B2M-HLA-G1s-Fc proteins.
<p>NFAT-GFP reporter cells expressing the ILT2-PILRβ chimera were stimulated for 16 h with 1.5 µg/ml of the indicated HLA-G recombinant proteins. Non-treated reporter cells were used as negative control, and tetrameric complexes of HLA-G1 (HLA-G1t, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0021011#pone.0021011-Liang2" target="_blank">[31]</a>) were used as positive control. GFP expression on reporter cells was analyzed by flow cytometry. Numbers indicate the percentage of GFP-positive cells. Data shown are from one of four independent experiments.</p
Primers used for fusion protein generation.
<p>Primers used for fusion protein generation.</p