title: CD80 and CD86 C domains play an important role in receptor binding and co-stimulatory properties.
abstract: CD80 and CD86 expressed on the surface of antigen-presenting cells interact with cytotoxic T lymphocyte antigen-4 [CTLA-4 (CD152)] expressed on activated T cells and mediate critical T cell inhibitory signals. CD80 and CD86 are type I glycoproteins, and are made up of two extracellular (EC) Ig-like domains-a transmembrane region and a cytoplasmic tail. The N-terminal (V domain) and membrane-proximal (C) domains share homology with the variable region (V) and the constant region (C) of Ig respectively. Co-crystallographic structures of both CD80 and CD86 bound to CTLA-4 indicate that there is no direct interaction of the C domain of either CD80 or CD86 with the CTLA-4. In contrast, previous mutagenesis studies have identified specific amino acids within the C domain of CD80 that are critical for CTLA-4 binding. To further understand the importance of C domains in the functioning of CD80 and CD86, we constructed chimeric human CD80 and CD86 molecules by swapping their respective C domains, and tested their ability to stimulate T cells. A Chinese hamster ovary (CHO) cell line expressing CD86 activated murine T cells. In contrast, CHO cells expressing either CD80 or a chimeric construct of the CD86 V domain and the CD80 C domain showed a significantly reduced activation. Our studies further demonstrated that the decreased activation by cells expressing the CD80 or a chimera containing CD80 C domain is most likely due to enhanced CTLA-4 binding. From these results we conclude that C domains play a critical, albeit indirect, role in determining CTLA-4 binding affinities and co-stimulatory properties.
authors.affiliation: Departments of Surgery, and Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Chenthamarakshan
authors.initials: C
authors.lastname: Vasu
authors.forename: Amy
authors.initials: A
authors.lastname: Wang
authors.forename: Seema R
authors.initials: SR
authors.lastname: Gorla
authors.forename: Shashi
authors.initials: S
authors.lastname: Kaithamana
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Holterman
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism*; D051940:B7-2 Antigen; D005260:Female; D007107:Immune System / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins