PhD Candidate University of Virginia, United States
Disclosure(s):
Sydney Blimbaum, MS: No financial relationships to disclose
Introduction/Rationale: Programmed cell death protein 1 (PD-1) is a well-studied regulator of T cell activation. It is also highly expressed on T follicular helper cells, and global deletion of PD-1 or its ligands, PD-L1 and PD-L2, has been shown to diminish antigen-specific B cell responses and formation of memory B cells. Given that PD-1 blockade immunotherapy has recently been associated with accelerated progression of atherosclerosis, we have developed a murine model with CD4-specific inducible loss of PD-1 to further investigate how PD-1 regulates the CD4 T cell, and consequently, the B cell response, both at baseline and in response to hyperlipidemia. We have also probed two cohorts of patients with coronary artery disease (CAD) to investigate the prevalence and phenotype of PD-1-expressing CD4 T cells among PBMCs.
Methods: To study loss-of-function in mice, we have generated CD4CreERT2Pdcd1fl/fl mice, with tamoxifen-inducible CD4-specific knockout of PD-1. In our human studies, we assembled a matched cohort of patients with low and high severity CAD, determined by coronary angiography, and performed CITE-Seq on PBMCs collected at the time of imaging.
Results: During hyperlipidemia, CD4-specific loss of PD-1 results in increased CD4 T cell activation and differentiation into Th subtypes, with corresponding decreases in the frequency of naïve CD4 T cells. We also observe increases in CXCR3 and CCR5 in CD4 T cells, both associated with trafficking to atherosclerotic lesions. In CAD patients, PD-1+ CD4s express these same markers. In the B cells, we observe major changes to B cell surface markers without PD-1 signaling, suggesting disruptions in T-dependent B cell activation.
Conclusion: Altogether, these data suggest that PD-1 is not only an important regulator of T cell activation, but also a regulator of T cell trafficking during atherosclerosis. Furthermore, the PD-1 signaling axis between CD4s and B cells may maintain B cell homeostasis.
