P2Y12 antagonism results in altered interactions between platelets and regulatory T cells during sepsis

Abstract

Abstract Sepsis is a complex clinical condition resulting from a serious bloodstream infection. With mortality rates as high as 50%, improved treatments are needed. Regulatory T cells (Tregs), a subset of T lymphocytes, promote the resolution of inflammation. Septic patients have elevated levels of circulating Tregs. Platelets influence the proliferation and activation of Tregs in vitro. However, modulating platelet-Tregs interaction during sepsis may restraing Treg proliferation, leading to the restoration of immunologic homeostasis. P2Y12 is a purinergic receptor present on platelets and T lymphocytes. Blocking P2Y12 improves the outcome of sepsis. We investigated whether blocking P2Y12 alters platelet–Treg interaction in vivo. We used the murine model of sepsis, cecal ligation, and puncture (CLP) and we blocked P2Y12 using the P2Y12 antagonist, clopidogrel. Twenty-four hours after surgery, we measured Treg population sizes in the spleens of the Sham, CLP, and CLP + clopidogrel groups. We investigated the effect of blocking P2Y12 in vitro using cocultures of human platelets and T cells with or without anti-CD3/CD28. P2Y12 was blocked using AR-C69931MX. Treg population sizes were reduced in the septic mice treated with clopidogrel compared with untreated septic mice. Aggregation of platelets and CD4+ T cells was reduced in treated CLP mice compared with untreated CLP mice. P2Y12 antagonism changes how platelets influence T cells in vitro, depending on T-cell activation. In conclusion, blockade of the P2Y12 signaling pathway restrains Treg proliferation in vivo and in vitro. Targeting platelets to control Treg proliferation and activity may be a promising strategy for treating sepsis.

Topics & Concepts