Induction of HLA-G-restricted human cytomegalovirus pp65 (UL83)-specific cytotoxic T lymphocytes in HLA-G transgenic mice.
The non-classical major histocompatibility complex class I molecule HLA-G is expressed mainly by extravillous trophoblasts at the materno-foetal interface. HLA-G has been found to bind endogenously processed nonameric peptides but its function as a restriction element for a cytotoxic T cell response to viruses with tropism for trophoblastic cells has never been demonstrated. In this study, candidate viral peptides derived from human cytomegalovirus (HCMV) pp65 (UL83), which stabilized the HLA-G molecule on HLA-G-transfected T2 cells, were identified. The specific anti-pp65 cytotoxic T lymphocyte (CTL) response restricted by HLA-G in triple transgenic mice (HLA-G, human beta2m, human CD8alpha) was then investigated by injection of dendritic cells loaded with synthetic pp65-derived peptides or by infection with canarypox virus expressing pp65. Results showed that CTLs from HLA-G mice have the capacity to kill target cells either infected with recombinant vaccinia viruses expressing pp65 or loaded with specific pp65-derived peptides using HLA-G as an antigen-presenting molecule. It was also demonstrated that these HLA-G-restricted pp65-specific T cells are able to kill the human astrocytoma cell line U373, which was transfected with HLA-G and infected with HCMV. Moreover, using HLA-G tetramers refolded with a synthetic pp65-derived peptide, peptide-specific CD8(+) cells restricted by HLA-G have been detected in vivo. These findings provide the first evidence that HLA-G can select anti-HCMV-restricted CTLs in vivo, although the potency of this cytolytic response is limited (20-25 %). The weak HLA-G-restricted anti-HCMV response is probably due to HLA-G-mediated inhibitory signals on the development of an antiviral CTL response.
Lenfant
Françoise
F
INSERM U 563, Centre de Physiopathologie de Toulouse Purpan, Hôpital Purpan, 31059 Toulouse cedex 3, France.
Pizzato
Nathalie
N
INSERM U 563, Centre de Physiopathologie de Toulouse Purpan, Hôpital Purpan, 31059 Toulouse cedex 3, France.
Liang
Siyuan
S
Program in Molecular Immunology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912-2600, USA.
Davrinche
Christian
C
INSERM U 563, Centre de Physiopathologie de Toulouse Purpan, Hôpital Purpan, 31059 Toulouse cedex 3, France.
Le Bouteiller
Philippe
P
INSERM U 563, Centre de Physiopathologie de Toulouse Purpan, Hôpital Purpan, 31059 Toulouse cedex 3, France.
Horuzsko
Anatolij
A
Program in Molecular Immunology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912-2600, USA.
D000818:Animals; D028121:Canarypox virus / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D022482:Cytomegalovirus Vaccines / Q000235:genetics / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
D022482:Cytomegalovirus Vaccines; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa