[The inhibitory effect of hyporesponsive peptide on human leukocyte antigen-DRbeta1 specific T cell activation].
OBJECTIVE
To evaluate the inhibitory effect of human leukocyte antigen (HLA)-DRbeta1 specific collagen II (CII) peptides with substitutions of TCR binding residues on T cell activation, and explore a new therapeutic strategy for T cell mediated autoimmune diseases by interfering with antigen recognition of T Cell receptor (TCR).


METHODS
Non-TCR binding peptides were designed by computer modeling based on interaction of HLA DR1. The modified CII263-272. Intracellular transfer of the modified CII peptide and its binding to HLA DR1 were studied using confocal microscopy and fluorescence-activated cell sorter (FACS). The effects of altered peptides on T cell activation were evaluated using an antigen presenting system consisting of HLA-DR1 transgenic APC and CII specific T cells.


RESULTS
Computer modeling showed the side chains of 263 (F), 266 (E) fit in the peptide binding groove, and form hydrogen bond with alpha1, beta1 chain of HLA-DR1. The side chains of TCR specific 267 (Q) and 270 (K) protruded out of the groove, which might be TCR recognizing residues. The modified CII peptides with intact HLA-DR1 binding residues were bound to intracellular HLA-DR1 and expressed on cell surface. The modified peptides with single residue substitution of 267-270 and consecutive substitution of 268-270 showed a hyporesponsive T cell activation. Altered peptides 270A, sub268-270 could significantly suppress the T cell activation induced by CII263-272.


CONCLUSIONS
The altered peptides with substitution of TCR binding residues are hyporesponsive in T cell activation, and may competitively inhibit the T cell activation in T cell mediated autoimmune diseases.
Zhou
Qiang
Q
Department of Rheumatology and Immunology, People's Hospital, Center of Health Sciences, Peking University, Beijing 100044, China.
Cheng
Yong-Jing
YJ
Li
Zhan-Guo
ZG
Zhou
Wei-Hong
WH
Lu
Hou-Shan
HS
D019943:Amino Acid Substitution; D024043:Collagen Type II / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D003198:Computer Simulation; D015798:HLA-DR1 Antigen / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D024043:Collagen Type II; D015798:HLA-DR1 Antigen; D015804:HLA-DR4 Antigen; D007166:Immunosuppressive Agents; D010455:Peptides; D011948:Receptors, Antigen, T-Cell