An evolutionary and functional analysis of the extended B7 family of costimulatory molecules

Thesis

T cell activation requires antigen-independent costimulatory signals induced by the interaction of costimulatory molecules on an antigen-presenting cell (APC) with their receptors on the T cell. CD28 and CTLA-4 are both expressed at the T cell surface and mediate positive and negative signals respectively when engaged by their APCexpressed ligands, B7-1 and B7-2.

This thesis establishes that the mouse orthologue of a third CD28-like molecule, ICOS, does not bind to mouse B7-1 and B7-2. To find a B7-like ICOS ligand, the sequence motifs defining the B7 family of molecules were established and used to identify new and distant family members in both the mouse and human. In the process, several new B7 family genes were found, including a mouse ligand for ICOS, called LICOS. The evolution of the B7 family was examined via phylogenetic analysis and linked to that of the human major histocompatibility complex. Cloning and preliminary characterisation of the new genes confirmed their relationship to B7 molecules, and demonstrated their expression in tissues of immunological interest.

The original members of the B7 family, B7-1 and B7-2, have been considered to have essentially equivalent binding properties. This view is challenged in this thesis through the analysis of the affinities and kinetics of the mouse B7 interactions using surface plasmon resonance-based methods. B7-1 and B7-2 were found to have different binding properties, including distinct preferences for binding to CD28 or CTLA-4. The conservation of these properties in the mouse underscores the significance of a new view of this system established in recent studies of the human orthologues. Finally, the focus is shifting toward understanding the nature of these interactions at the T cell/APC interface. To initiate work in this area, a new bioluminescence-based assay was evaluated and used to characterise the selfassociation of B7-1 at the cell surface.

Authors: Iaboni, A; Iaboni, Andrea

• Publication date: 2002
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Receptors; Major histocompatibility complex; T cells