Robinson, Maximillian Aynsley; (2024) Characterising the Molecular Interactions Between the CTLA-4 and PD-1 Pathways. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

T-cell activation is a crucial step in the induction of optimal immune responses. CD28 is the primary co-stimulatory molecule expressed on most T-cells, which, alongside competent TCR signals, induces potent activation following ligation by either ligand CD80 or CD86. Conversely, CTLA-4 is a critical inhibitory co-receptor which also binds CD80 and CD86, and functions by regulating the amount of co- stimulation available for T-cell activation. In addition, PD-1 is a separate inhibitory co-receptor which, upon ligation with PD-L1, inhibits T-cell responses by attenuat- ing membrane proximal TCR and CD28 signals. Recent evidence indicates that CD80 and PD-L1, the ligands for CTLA-4 and PD-1 respectively, interact when both are co-expressed at the cell membrane, i.e., in cis. Early reports suggest that CD80 – PD-L1 interactions antagonise PD-1 binding, thereby placing CD80 as a regulator of the PD-1 pathway. However, the impact of the cis interaction on CTLA-4 and CD28 biology is poorly understood. Herein we examined the molecular characteristics of the CD80 – PD-L1 inter- action with regards to the CTLA-4 and CD28 pathway. First, we demonstrated that CD80 and PD-L1 interact in cis, thereby preventing PD-1 binding and subse- quent PD-1-mediated inhibition, in line with the recent literature. In contrast to PD-1, we observed that CD28 and CTLA-4 binding to CD80 is unimpeded by PD- L1 co-expression and, moreover, that soluble CTLA-4 binding disrupts the CD80 – PD-L1 heterodimer under certain conditions. Through the generation of soluble CTLA-4 variants we identified that both the bivalency and rigidity of the CTLA-4 molecule was required to disrupt the CD80 – PD-L1 heterodimer. Finally, we ob- served that CTLA-4-mediated trans-endocytosis of CD80 released PD-1-competent PD-L1. These data suggest a molecular model where CTLA-4 controls levels of PD- 1 inhibition through the physical removal of CD80 and subsequent PD-L1 release, a process dependent upon the bivalency and rigid structure of the CTLA-4 molecule.

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