A Transendocytosis model of CTLA-4 function predicts its suppressive behaviour on regulatory T cells

Research output: Contribution to journalArticle

Abstract

Manipulation of the CD28/CTLA-4 pathway is at the heart of a number of
immunomodulatory approaches used in both autoimmunity and cancer. Whilst
it is clear that CTLA-4 is a critical regulator of T cell responses, the
immunological contexts in which CTLA-4 restricts immune responses are not
well defined. Here we demonstrate that CD80/CD86-dependent activation of
resting human T cells caused extensive T cell proliferation in spite of robust
CTLA-4 expression in all dividing T cells. In this context, CTLA-4 blocking
antibodies had no impact on T cell responses. In contrast, in settings where
CTLA-4+ cells were present as 3rd party “regulators”, inhibition of resting T cell
responses was dependent on CTLA-4 expression and specifically related to
the number of antigen presenting cells. At low numbers of APC or low levels of
ligand, CTLA-4-dependent suppression was highly effective whereas at higher
APC numbers or high levels of ligand, inhibition was lost. Accordingly, the
degree of suppression correlated with the level of CD86 expression remaining
on the antigen presenting cells. Importantly, CTLA-4 based suppression did
not require a specialised cell type and could be mediated by CTLA-4
expressing Treg, as well as by other CTLA-4 expressing cells. These data
reveal that the inhibitory function of CTLA-4 on Treg is accurately predicted by
its ability to remove ligands from antigen presenting cells.

Details

Original languageEnglish
Pages (from-to)2148-2159
JournalJournal of Immunology
Volume194
Issue number5
Publication statusPublished - 2015