CD28 costimulation in T cells: requirements, outcomes and regulation

R Medicine > R Medicine (General)

Briggs , Zoe Louise ; Sansom, David

University:University of Birmingham

Department:School of Immunity and Infection

关键词: R Medicine;    R Medicine (General);   

Others  :  http://etheses.bham.ac.uk//id/eprint/5378/1/Briggs14PhD.pdf

来源: University of Birmingham eTheses Repository

【 摘 要 】

The costimulatory receptor CD28 and its inhibitory counterpart CTLA-4 share the same ligands and comprise a crucial checkpoint in T cell activation. CTLA-4 removes its ligands from antigen presenting cells by trans-endocytosis, which reduces the availability of costimulatory ligands for CD28 engagement to regulate T cell activation. This project examined the functional implications of reducing the availability of costimulatory molecules for CD4 T cell responses, and investigated the use of trans-endocytosis by other T cell receptors. Surprisingly, it was revealed that PD-1 and OX40 can also internalise their ligands, although perhaps not via the same mechanism as CTLA-4 trans-endocytosis. It was also shown that altering the availability of CD28 ligands affects the extent of T cell proliferation, suggesting that CTLA-4 trans-endocytosis can finely tune the T cell response. Furthermore, it was observed that CD28 costimulation is not always required for T cell activation and proliferation, but CD28 engagement is required for the optimal upregulation of a number of effector proteins and for TH2 cytokine production. Interestingly, T cells activated in the absence of CD28 signalling were not classically anergic. Strikingly, it was also found that memory T cells are dependent on CD28 costimulation.