Ovcinnikovs, Vitalijs; (2018) CTLA-4-mediated Trans-endocytosis in the Control of T Cell Co-stimulation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The signal threshold for the activation of a naïve T cell upon recognising its antigen is regulated tightly by the CD28/CTLA-4 – CD80/86 pathway. Within this framework, CTLA-4 has been shown to limit the availability of co-stimulation by physical removal of CD80 and CD86 from the APC, via the mechanism of trans-endocytosis (TE). The study presented in this thesis explores CTLA-4-mediated modulation of CD80 and CD86 as it occurs in vitro and in vivo. It is revealed that regulatory T cells, highly enriched in CTLA-4, are able to rapidly recruit it to the cell surface and trans-endocytose CD80 and CD86 upon stimulation. As a result, Treg, but not Tconv, within hours can significantly reduce the level of co-stimulation on DCs. Although both CD80 and CD86 can be readily taken up by CTLA-4, CD80 is the dominant ligand that it preferentially downregulated from APCs in a competitive scenario. Furthermore, CD28 signalling, in addition to TCR, is identified as a requirement for effective CTLA-4 function. In vivo, co-stimulation is shown to dictate the magnitude of a T cell response in a digital manner. Accordingly, Treg suppress Tconv expansion in a way that is consistent with reduced co-stimulation as a consequence of TE. By using antigen presenting cells that express fluorescently-tagged CD80 and CD86, it is revealed that Treg use CTLA-4 to capture its ligands across tissues in the steady state. Thereby, the phenotype of the APC is constantly modulated. Perturbing CTLA-4 identifies that the lymph node migratory DCs are the main target for CTLA-4 control, while CD80 is confirmed to be the preferred ligand. Finally, Treg-expressed CD80 and CD86 is shown to act as a tuning mechanism that restricts homeostatic activation, suppressive capability and TE. Together, these data provide new insight into how CTLA-4-mediated trans-endocytosis may routinely prevent self-reactive immune activation.

Type:	Thesis (Doctoral)
Qualification:	Ph.D
Title:	CTLA-4-mediated Trans-endocytosis in the Control of T Cell Co-stimulation
Event:	UCL (University College London)
Language:	English
UCL classification:	UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI:	https://discovery.ucl.ac.uk/id/eprint/10059309

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