Discrepancy in CD3-transmembrane peptide activity between in vitro and in vivo T-cell inhibition.
Electrostatic amino acid interactions between receptor subunits within the T-cell antigen receptor (TCR) transmembrane domain are critical for the formation of the TCR-CD3 complex. Core peptide, a short peptide corresponding to the TCR-alpha transmembrane region, containing two positively charged amino acids, is known to inhibit T-cell function in vitro and in vivo. The aim of this study was to examine peptides corresponding to the syntactic transmembrane CD3 region binding to TCR-alpha for their ability to inhibit T-cell activation in vitro and in vivo. Three peptides matching the transmembrane sequence of CD3-delta, -epsilon and -gamma were synthesized and tested in different biological in vitro and in vivo systems for their effect on T-cell activity. The CD3-peptides had no impact on T-cell function in vitro, but surprisingly, decreased signs of inflammation in the adjuvant arthritis rat model in vivo. Preliminary evidence suggests that peptides with CD3 transmembrane-derived sequences can inhibit an immune response as assessed by adjuvant-induced arthritis. The lack of in vitro activity may lead to a wasteful disregard of active compounds in the process of drug discovery and development.
Collier
S
S
Department of Rheumatology, Westmead Hospital, Westmead, NSW, Australia.
Bolte
A
A
Manolios
N
N
D000818:Animals; D045744:Cell Line, Tumor; D006825:Hybridomas; D007166:Immunosuppressive Agents / Q000378:metabolism; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D010446:Peptide Fragments; D017260:Receptor-CD3 Complex, Antigen, T-Cell