The soluble cytoplasmic tail of CD45 (ct‐CD45) in human plasma contributes to keep T cells in a quiescent state

Abstract

The cytoplasmic tail of CD45 (ct‐CD45) is proteolytically cleaved and released upon activation of human phagocytes. It acts on T cells as an inhibitory, cytokine‐like factor in vitro. Here, we show that ct‐CD45 is abundant in human peripheral blood plasma from healthy adults compared with plasma derived from umbilical cord blood and plasma from patients with rheumatoid arthritis or systemic lupus erythematosus. Plasma depleted of ct‐CD45 enhanced T‐cell proliferation, while addition of exogenous ct‐CD45 protein inhibited proliferation and reduced cytokine production of human T lymphocytes in response to TCR signaling. Inhibition of T‐cell proliferation by ct‐CD45 was overcome by costimulation via CD28. T‐cell activation in the presence of ct‐CD45 was associated with an upregulation of the quiescence factors Schlafen family member 12 (SLFN12) and Krueppel‐like factor 2 (KLF2) as well as of the cyclin‐dependent kinase (CDK) inhibitor p27kip1. In contrast, positive regulators of the cell cycle such as cyclin D2 and D3 as well as CDK2 and CDK4 were found to be downregulated in response to ct‐CD45. In summary, we demonstrate that ct‐CD45 is present in human plasma and sets the threshold of T‐cell activation.

Inhibition of CD45 Phosphatase Activity Induces Cell Cycle Arrest and Apoptosis of CD45+ Lymphoid Tumors Ex Vivo and In Vivo

“…The mechanism of cell death involves dysregulation of Lck and inappropriate activation, leading to cell cycle arrest and ending in apoptosis/necrosis. Other studies have reported that dysregulation of CD45 using mAbs or soluble CD45 enzyme can result in cell death or lack of differentiation/ growth (Robson et al, 1996;Harashima et al, 2002;Puck et al, 2017). However, to the best of our knowledge, our study is the first to associate inhibition of CD45 activity and cell cycle arrest, a mechanism that leads to cell death.…”

Schlafen 12 Interaction with SerpinB12 and Deubiquitylases Drives Human Enterocyte Differentiation

“…SLFN12 has previously been reported to alter the phenotype of other cells, including prostatic cancer cells [53] and activated T cells [54, 55], and to inhibit dendritic cell differentiation [11]. Slfn4, also intermediate length, regulates myelopoiesis [56].…”

Iron Deprivation in Human T Cells Induces Nonproliferating Accessory Helper Cells

“…After 3 d, cells were harvested and fixed using 70% ethanol at 4°C for 30 min. After washing, cells were stained with 50 mg/ml propidium iodide in the presence of 100 mg/ml RNAse A for 45 min at room temperature, as recently described (21). DNA content was then measured on a BD FACSCalibur Flow Cytometer and analyzed via CellQuest (BD Biosciences).…”

“…Supernatants were cleared from residual mAbs by overnight incubation (4°C) with Dynabeads M-280 sheep anti-mouse IgG (Thermo Fisher Scientific), followed by removal of complexes via centrifugation, as previously described (21,22). Part of the cleared supernatant was then treated with anti-IL-2 mAb clone no.…”