CD80 and CD86 IgC domains are important for quaternary structure, receptor binding and co-signaling function.
CD86 and CD80, the ligands for the co-stimulatory molecules CD28 and CTLA-4, are members of the Ig superfamily. Their structure includes Ig variable-like (IgV) domains, Ig constant-like (IgC) domains and intracellular domains. Although crystallographic studies have clearly identified the IgV domain to be responsible for receptor interactions, earlier studies suggested that both Ig domains are required for full co-signaling function. Herein, we have used deletion and chimeric human CD80 and CD86 molecules in co-stimulation assays to study the impact of the multimeric state of IgV and IgC domains on receptor binding properties and on co-stimulatory function in a peptide-specific T cell activation model. We report for the first time the presence of CD80 dimers and CD86 monomers in living cells. Moreover, we show that the IgC domain of both molecules inhibits multimer formation and greatly affects binding to the co-receptors CD28 and CTLA-4. Finally, both IgC and intracellular domains are required for full co-signaling function. These findings reveal the distinct but complementary roles of CD80 and CD86 IgV and IgC domains in T cell activation.
Department of Microbiology and Immunology, McGill University, Montréal, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc, Montréal, Québec, Canada.
Tanya
T
Girard
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc, Montréal, Québec, Canada; Département de Microbiologie et Immunologie, Université de Montréal, Montréal, Canada.
Denis
D
Gaucher
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc, Montréal, Québec, Canada; Département de Microbiologie et Immunologie, Université de Montréal, Montréal, Canada.
Mohamed
M
El-Far
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc, Montréal, Québec, Canada; Département de Microbiologie et Immunologie, Université de Montréal, Montréal, Canada.
Gaëlle
G
Breton
Department of Microbiology and Immunology, McGill University, Montréal, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc, Montréal, Québec, Canada; Département de Microbiologie et Immunologie, Université de Montréal, Montréal, Canada; Vaccine and Gene Therapy Institute Florida, Port St. Lucie, FL, United States. Electronic address: rpsekaly@vgtifl.org.
Rafick-Pierre
RP
Sékaly
D018122:B7-1 Antigen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051940:B7-2 Antigen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018106:CD28 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017384:Sequence Deletion; D015398:Signal Transduction
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D007376:Interleukin-2
CD80; CD86; CTLA-4; Immunoglobulin; T cells