eprintid: 10046608
rev_number: 58
eprint_status: archive
userid: 608
dir: disk0/10/04/66/08
datestamp: 2018-05-23 11:27:00
lastmod: 2020-02-12 21:53:01
status_changed: 2018-05-23 11:27:00
type: thesis
metadata_visibility: show
creators_name: Wang, Chunjing
title: Role of CTLA-4 in CD4 T cell Homeostasis, Function and Differentiation
ispublished: unpub
divisions: UCL
divisions: A01
divisions: B02
divisions: C10
divisions: D15
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.
date: 2018-04-28
date_type: published
full_text_type: other
thesis_class: doctoral_md_only
thesis_award: Ph.D
language: eng
thesis_view: UCL_Thesis
verified: verified_manual
elements_id: 1548691
lyricists_name: Wang, Chunjing
lyricists_id: CWANA42
actors_name: Dewerpe, Marie
actors_id: MDDEW97
actors_role: owner
full_text_status: none
pages: 208
event_title: UCL (University College London)
institution: UCL (University College London)
department: Department of Immunology; Division of Infection and Immunity
thesis_type: Doctoral
citation:        Wang, Chunjing;      (2018)    Role of CTLA-4 in CD4 T cell Homeostasis, Function and Differentiation.                   Doctoral thesis  (Ph.D), UCL (University College London).