Peptide-dependent inhibition of alloreactive T-cell response by soluble divalent HLA-A2/IgG molecule in vitro.
BACKGROUND
Induction of peripheral tolerance in an antigen-specific manner is a critical goal of transplant biology. The specificity and avidity of multimerized peptide/major histocompatibilty complexes suggest their potential ability to modulate antigen-specific T-cell sensitization and effector functions.


METHODS
A soluble divalent HLA-A2/IgG molecule (HLA-A2 dimer) was constructed and loaded with a self-protein origin peptide (Tyr(368-376)) to form a divalent Tyr/HLA-A2 molecule (Tyr/HLA-A2 dimer), which allowed for specific targeting to the epitope-specific cytotoxic T lymphocytes in bulk alloreactive T cells. Alloreactive T-cell response was induced by coculture of Tyr(368-376) -pulsed T2 cells (T2/Tyr) with peripheral blood lymphocytes of HLA-A2-negative (HLA-A2-ve) sample; five samples of HLA-A2-ve individuals were included in this study. After the coculture in the presence of Tyr/HLA-A2 dimer, the suppression of the dimer on alloresponse was characterized by analyzing allogeneic T-cell proliferation, specific cytolytic activity against the T2/Tyr, and specific Tyr/HLA-A2 tetramer staining.


RESULTS
The Tyr/HLA-A2 dimer suppresses alloreactive T-cell response by inhibiting its proliferation and cytotoxicity against specific target T2/Tyr in vitro, and it is interesting that the suppression is peptide-specific. The Tyr/HLA-A2 tetramer staining suggests the reduced function of CD8+ T cell is caused by inhibiting the generation of the epitope-specific alloreactive T cells by the Tyr/HLA-A2 dimer in three samples. Moreover, the existence of epitope-specific but function-negative T cells in the other two samples suggests that another mechanism might exist that is involved in silencing alloreactive responses by the dimer.


CONCLUSIONS
Peptide-loaded dimers offer a novel approach to induce peptide-specific immunosuppression and may be useful in promoting graft survival.
Department of Immunology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
Xiufang
X
Weng
Maohua
M
Zhong
Zhihui
Z
Liang
Shenjun
S
Lu
Juan
J
Hao
Xueling
X
Chen
Jianan
J
Li
Feili
F
Gong
Xiongwen
X
Wu
D002460:Cell Line; D002999:Clone Cells / Q000187:drug effects / Q000276:immunology; D019281:Dimerization; D015789:HLA-A2 Antigen / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D015789:HLA-A2 Antigen; D007074:Immunoglobulin G