Wang, Chunjing;
(2018)
Role of CTLA-4 in CD4 T cell Homeostasis, Function and Differentiation.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
CTLA-4, as a member of CD28 receptor family, has been widely accepted as an important negative regulator of immune responses and plays an essential role in maintaining self-tolerance. Accordingly congenital ablation of the CTLA-4 gene in mice causes uncontrolled lymphoproliferation and extensive autoimmune tissue destruction. Here we demonstrate that CTLA-4 deficiency not only results in hyperactivated conventional T cells, but also causes an increased regulatory T cell (Treg) compartment, which can be largely attributed to enhanced proliferation of Treg in the periphery. Through short-term anti-CTLA-4 antibody treatment of wildtype and CD28-deficient mice, we reveal CTLA-4-mediated control of Treg proliferation is dependent on control of CD28 signaling. In addition to regulating Treg proliferation, data from an adoptive transfer model of type 1 diabetes suggests CTLA-4 is an important component of Treg suppression in vivo. For years, CTLA-4 was thought to function extrinsically in Treg but intrinsically in conventional T cells. In this project, we show CTLA-4 expressed on conventional T cells can also work in a cell extrinsic manner. In this way, antigen-specific-CTLA-4-sufficient conventional T cells can restrain the proliferative responses of CTLA-4-deficient ones upon co-transfer. However CTLA-4-sufficient conventional T cells cannot replace Treg for the maintenance of peripheral tolerance. Accordingly, CTLA-4-sufficient conventional T cells only partially control lymphoproliferative disease induced by CTLA-4-/- bone marrow cells whereas its-sufficient Treg completely prevent disease in this setting. In addition, we demonstrate that the CTLA-4/CD28 pathway also plays a key role in controlling follicular helper T cell differentiation and subsequently germinal center B cell development. Taken together, our data in this study yield new insights into how the CTLA-4 pathway controls immune responses in vivo.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Role of CTLA-4 in CD4 T cell Homeostasis, Function and Differentiation |
| Event: | UCL (University College London) |
| Language: | English |
| UCL classification: | UCL 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-pp.ucl.ac.uk/id/eprint/10046608 |
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