Accruing evidence signify that people with CF (pwCF) generate insufficient T-cell responses that contribute to support
the excessive inflammation. Among others, platelets (PLT) are key players of CF inflammation since they could alter the
response of a variety of immune cells including CD8 T lymphocytes.
Thus, central hypothesis of the proposed research is that PLT dampen CD8 actions to fuel CF inflammation. Targeting
PLT-CD8 crosstalk could be beneficial.
The proposed research will address the following objectives:
1. Determine how PLT affect CD8
2. Evaluate the impact of PLT-CD8 crosstalk on airway inflammation
3. Test strategies to promote CD8 re-activation and resolution of inflammation
Our ongoing work highlights increased circulating PLT/CD8 aggregates in pwCF as compared to healthy donors (HD)
due to PLT hyperactivity. CF CD8 in PLT/CD8 express high levels of exhaustion markers and lower cytotoxic ability.
Thus, PLT stimulate differentiation of CD8 toward dysfunction. In vivo, PLT/CD8 are detected in airway of mice after
bacterial challenge, suggestive of a role in infected airways.
In Aim1 (1st year), using blood cells from pwCF and HD, we will establish how PLT hinder CD8 by investigating effector
function, expression of inhibitory receptors, transcriptional profiles, and chromatin proteome in PLT/CD8.
In Aim 2 (2nd year), we will detail the contribution of PLT-CD8 crosstalk in inflammation and infection in vitro
(airways-on-chip) and in vivo (chronic S.aureus in mice with PLT or CD8 depletion).
In Aim 3 (3rd year), CFTR KO mice and purified human cells will be used to test whether targeting PLT with Resolvin
D3 or PLT/CD8 interaction with immune checkpoint inhibitors (ICI) could reinvigorate CD8 and promote resolution of
inflammation.
Completion of these experiments will establish a) how CF PLT alter CD8; b) the impact of CD8 in airway inflammation;
c) if anti-PLT or ICI restore an effective CD8 response in CF; d) a list of additional targets to circumvent the PLTmediated
CD8 dysfunction.
These studies are considerably relevant to the FFC mission (to promote innovative treatment and care for CF) since will
investigate innovative strategies to restrain the inflammation-based pathology targeting a previously unexplored
pathological mechanism. This proposal will also shed more light into functions of adaptive cells in CF, paving the way
for new research aimed at dissecting the role of CF lymphocytes.