Increased Soluble CD137 Levels and CD4+ T‐Cell‐Associated Expression of CD137 in Acute Atherothrombotic Stroke

Abstract

As a proinflammatory cytokine, CD137 (4‐1BB, TNFRSF9) is present in membrane‐bound and soluble forms. Increased expression of CD137 was recently found in T cells in human atherosclerotic plaques. However, the exact role of CD137 in ischemic stroke is not clear. In this study we analyzed the protein levels of soluble CD137 (sCD137) and the expression of CD137 on CD4+ T cells in the peripheral blood of patients with acute atherothrombotic stroke by using the cytometry beads array (CBA) and flow cytometry. Within 24 hours of onset, the stroke patients showed elevated levels of sCD137 (2.7 pg/ml) and CD137 expression on CD4+ T cells (4.9 ± 3.2%) compared with normal controls (1.1 pg/ml, P < 0.01; 1.3 ± 1.0%, P < 0.01). Alterations in CD137 expression may enhance ischemia‐induced inflammatory responses via bidirectional signaling and, consequently, aggravate brain injury in early stages of this disorder.

Multivariate Computational Analysis of Gamma Delta T Cell Inhibitory Receptor Signatures Reveals the Divergence of Healthy and ART-Suppressed HIV+ Aging

“…As an indirect measurement of the potential in vivo functional activity of the γδ T cells, cells were sorted and cultured overnight without stimulation and the secretion of 33 analytes was measured in the supernatants. The spontaneous release of sCD137, a marker of cell activation that correlates with circulating C-reactive protein (CRP) in plasma (66) and is positively associated with both acute coronary syndromes (66) and stroke (67), was significantly higher from the γδ T cells of HIV+ older subjects compared with the other three groups (Figure 4A, results from the other detected analytes are shown in Supplementary Figure 4). As each sample stained with the 16-color panel was run through the FACSARIA cell sorter, the percentages of TIGIT+ γδ T cells were determined and the γδ T cells were sorted for cell culture simultaneously.…”

“…sCD137 is a pro-inflammatory molecule that can be produced as an alternatively spliced variant or by proteolytic cleavage of CD137 (4-1BB) (114), a member of TNF superfamily, and a marker associated with multiple inflammatory diseases. sCD137 plasma levels positively associate with acute coronary syndromes (66) and atherothrombotic stroke (67), and we hypothesize that in vivo , γδ T cells produce sCD137 which is also known to trigger pro-inflammatory networks that involve macrophages and DCs (115) Also, our multivariate PSLR results (Figures 4D,E, and Figures 5F,G) show that the relationships between γδ IR signatures and both the cytokines they produce and plasma markers with which they co-vary are different in the younger vs. older subjects in both the uninfected control and HIV+ groups, since the younger and older subjects separated in all four PLSR models without age being added as a variable. These results show that there are distinct aging courses in relation to immune network changes with and without HIV infection.…”

The relevance of soluble CD137 in the regulation of immune responses and for immunotherapeutic intervention

“…Several groups have demonstrated the association between sCD137 and active inflammatory states in several diseases. For instance, higher levels of sCD137 in patients’ plasma were reported in many autoimmune diseases, acute atherothrombotic stroke, acute coronary syndrome, and acute pancreatitis . In obesity sCD137 was postulated to be a cause of inflammation, and it was shown that inhibiting sCD137 could reverse inflammation .…”

Multivariate Computational Analysis of Gamma Delta T cell Inhibitory Receptor Signatures Reveals the Divergence of Healthy and ART-Suppressed HIV+ Aging

“…As an indirect measurement of the potential in vivo functional activity of the γδ T cells, cells were sorted and cultured overnight without stimulation and the secretion of 33 analytes was measured in the supernatants. The spontaneous release of sCD137, a marker of cell activation that correlates with circulating C-reactive protein (CRP) in plasma [65] and is positively associated with both acute coronary syndromes [65] and stroke [66], was significantly higher from the γδ T cells of HIV+ older subjects compared with the other three groups (Fig. 4A, results from the other detected analytes are shown in Supplemental Fig.…”

“…sCD137 is a pro-inflammatory molecule that can be produced as an alternatively spliced variant or by proteolytic cleavage of CD137 (4-1BB) [112], a member of TNF superfamily, and a marker associated with multiple inflammatory diseases. sCD137 plasma levels positively associate with acute coronary syndromes [65] and atherothrombotic stroke [66], and we hypothesize that in vivo, γδ T cells produce sCD137 which is also known to trigger pro-inflammatory networks that involve macrophages and DCs [113] Also, our PSLR results show that the relationships between γδ IR signatures and both the cytokines they produce and plasma markers with which they co-vary are different in the younger versus older subjects in both the uninfected control and HIV+ groups, since the younger and older subjects separated in our PLSR models without age being added as a variable. These results show that there are distinct aging courses in relation to immune network changes with and without HIV infection.…”