Depletion of CD4 and CD8 Positive T Cells Impairs Venous Thrombus Resolution in Mice

Abstract

Resolution of deep venous thrombosis involves coordinated inflammatory processes. T cells regulate inflammation in vivo and modulate vascular remodeling in other settings, but their role in venous thrombus resolution remains undefined. To determine the role of T cells in venous thrombus resolution in vivo, stasis induced thrombi were created by vena cava ligation in outbred CD-1 mice. CD4 and CD8 positive T cells, as determined by flow cytometry, were present in thrombi both during thrombus formation and resolution. Depletion of the CD4 and CD8 positive T cells by antibody treatment selectively impaired thrombus resolution compared to animals treated with isotype control antibodies, without an effect on venous thrombus formation. Quantitation of intra-thrombus macrophage numbers, fibrinolytic marker expression, and gelatinolytic activity by zymography revealed that T cell depletion decreased the number of macrophages, reduced the expression of fibrinolytic marker urokinase plasminogen activator (uPA), and decreased the activity of matrix metalloprotinease-9 (MMP-9). These data implicate CD4 and CD8 positive T cells in functionally contributing to venous thrombus resolution, thus representing a potential therapeutic target, but also underscoring potential risks involved in T cell depletion used clinically for solid organ and hematopoietic transplantation procedures.

S100b in acute ischemic stroke clots is a biomarker for post-thrombectomy intracranial hemorrhages

“…Main cellular drivers of this process are platelets and innate immune cells, primarily neutrophils and monocytes which interplay with platelets and flanked by the activation of the complement system promote coagulation ( 62 ). T-lymphocytes play a major role in the initiation and perpetuation of inflammatory cascades as well, involving crosstalk with other immune cells, especially by modulating macrophage response ( 63 ), although their specific role in thrombus formation is still unclear ( 64 ).…”

Deficiency in CD4 T Cells Leads to Enhanced Postpartum Internal Carotid Artery Vasoconstriction in Mice: The Role of Nitric Oxide

“…In general, deficiency in T cells and B cells in mouse models is associated with differences in microvascular arteriolar baseline diameter and reactivity to vasoconstrictors and vasodilators ( Leonard et al, 2011 ; Mukhopadhyay et al, 2020 ). During pregnancy this results in mid-gestational differences in heart rate and mean arteriolar pressure, thus suggesting that these cell subsets may influence systemic vascular biology in the mother both developmentally and during pregnancy ( Burke et al, 2011 ).…”

Multiple Facets of Venous Thrombosis

“…In this Special Issue, works from different groups are presented uncovering new aspects of DVT or summarizing existing knowledge on the topic. Whereas the role of the innate immune system in DVT has been reported [ 5 , 6 ], Mukhopadhyay and colleagues demonstrate previously underestimated involvement of the adaptive immune system in thrombus resolution [ 7 ]. These authors show that depletion of T-cells unexpectedly reduces the numbers of macrophages in the thrombus and decreases activity of the fibrinolytic system and metalloproteinase-9, involved in thrombus dissolution.…”