Title : Hierarchical regulation of
CTLA-4 dimer-based lattice formation and its biological relevance for T cell inactivation
Abstract :
- CTLA-4 is an activation-induced, homodimeric inhibitory receptor in T cells
- Recent crystallographic reports have suggested that it may form lattice-like arrays on the cell surface upon binding B7.1/B7.2 ( CD80 , CD86 ) molecules
- To test the biological relevance of these CTLA-4-B7 lattices, we introduced a C122A point mutation in human CTLA-4 , because this residue was shown to be essential for dimerization in solution
- Surprisingly, we found that up to 35% of C122A CTLA-4 dimerized in human T lymphocytes
- Moreover, C122A CTLA-4 partitioned within lipid rafts, colocalized with the TCR in the immunological synapse, and inhibited T cell activation
- C122-independent dimerization of CTLA-4 involved N-glycosylation, because further mutation of the N78 and N110 glycosylation sites abrogated dimerization
- Despite being monomeric, the N78A/N110A/C122A triple mutant CTLA-4 localized in the immunological synapse and inhibited T cell activation
- Such functionality correlated with B7-induced dimerization of these mutant molecules
- Based on these data, we propose a model of hierarchical regulation of CTLA-4 oligomerization by which B7 binding ultimately determines the formation of dimer-dependent CTLA-4 lattices that may be necessary for triggering B7-dependent T cell inactivation