Abstract
CD28, CTLA-4 and PD-L1, the three identified ligands for CD80/86, are pivotal positive and negative costimulatory molecules that, among other functions, control T cell motility and formation of immune synapse between T cells and antigen-presenting cells (APCs). What remains incompletely understood is how CD28 leads to the activation of effector T cells (Teff) but inhibition of suppression by regulatory T cells (Tregs), while CTLA-4 and PD-L1 inhibit Teff function but are crucial for the suppressive function of Tregs. Using alloreactive human T cells and blocking antibodies, we show here by live cell dynamic microscopy that CD28, CTLA-4, and PD-L1 differentially control velocity, motility and immune synapse formation in activated Teff versus Tregs. Selectively antagonizing CD28 costimulation increased Treg dwell time with APCs and induced calcium mobilization which translated in increased Treg suppressive activity, in contrast with the dampening effect on Teff responses. The increase in Treg suppressive activity after CD28 blockade was also confirmed with polyclonal Tregs. Whereas CTLA-4 played a critical role in Teff by reversing TCR-induced STOP signals, it failed to affect motility in Tregs but was essential for formation of the Treg immune synapse. Furthermore, we identified a novel role for PD-L1-CD80 interactions in suppressing motility specifically in Tregs. Thus, our findings reveal that the three identified ligands of CD80/86, CD28, CTLA-4 and PD-L1, differentially control immune synapse formation and function of the human Teff and Treg cells analyzed here. Individually targeting CD28, CTLA-4 and PD-L1 might therefore represent a valuable therapeutic strategy to treat immune disorders where effector and regulatory T cell functions need to be differentially targeted.
Highlights
The interaction of CD80/86 and their receptors are important co-stimulatory and co-inhibitory pathways that were shown to regulate Teff responses and peripheral immune tolerance, in particular by controlling Treg development, function and homeostasis
CD28, CTLA-4 and PD-L1 are the three ligands identified on T cells so far that are binding to CD80/86 on human antigenpresenting cells (APCs) [1,2,3]
It has been reported that interactions between Programmed cell death 1 (PD-1) and PD-L1 participate in the maintenance of peripheral tolerance by reducing T cell-dendritic cell (DC) contacts [15]
Summary
The interaction of CD80/86 and their receptors are important co-stimulatory and co-inhibitory pathways that were shown to regulate Teff responses and peripheral immune tolerance, in particular by controlling Treg development, function and homeostasis. By controlling T cell motility and activation, these molecules determine whether contacts between conventional effector T cells (Teff) and APCs result in the formation of immunological synapses and in T cell responses [4]. Programmed cell death 1 ligand 1 (PD-L1, known as CD274 or B7-H1, B7 homolog 1) is inducibly expressed on T cells and can interact with CD80 with an affinity intermediate to that of CD28 and CTLA-4 in humans, resulting in inhibition of T cell proliferation and cytokine production [14]. It has been reported that interactions between Programmed cell death 1 (PD-1) and PD-L1 participate in the maintenance of peripheral tolerance by reducing T cell-dendritic cell (DC) contacts [15]
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