Human memory T cells from the bone marrow are resting and maintain long-lasting systemic memory.

In the bone marrow, a population of memory T cells has been described that promotes efficient secondary immune responses and has been considered to be preactivated, owing to its expression of CD69 and CD25. Here we show that human bone marrow professional memory T cells are not activated but are resting in terms of proliferation, transcription, and mobility. They are in the G0 phase of the cell cycle, and their transcriptome is that of resting T cells. The repertoire of CD4(+) bone marrow memory T cells compared with CD4(+) memory T cells from the blood is significantly enriched for T cells specific for cytomegalovirus-pp65 (immunodominant protein), tetanus toxoid, measles, mumps, and rubella. It is not enriched for vaccinia virus and Candida albicans-MP65 (immunodominant protein), typical pathogens of skin and/or mucosa. CD4(+) memory T cells specific for measles are maintained nearly exclusively in the bone marrow. Thus, CD4(+) memory T cells from the bone marrow provide long-term memory for systemic pathogens.

Human bone marrow contains a subset of quiescent early memory CD8(+) T cells characterized by high CD127 expression and efflux capacity.

Even today it is still not completely understood how CD8(+) T-cell memory is maintained long term. Since bone marrow (BM) is a niche for immunological memory, we sought to identify long-lasting early memory CD8(+) T cells in this compartment. To achieve this, we looked for CD8(+) T cells that are able to efflux Rhodamine 123, a typical property of stem cells. Indeed, we identified a distinct subset of CD8(+) T cells in BM, with the capacity to efflux and high CD127 expression. These CD127(hi) effluxers are conventional CD8(+) T cells exhibiting a broad TCR-Vß repertoire and are generated in response to viral peptides in vitro. CD127(hi) effluxer CD8(+) T cells have an early memory phenotype defined by preferential TNF-α production and a Bcl-2(hi) , KLRG-1(low) profile. This population has long telomeres and shows constitutively low frequencies of Ki-67 expression ex vivo, but has a high proliferative and differentiation capacity in vitro. However, IL-15 downmodulates CD127 in CD127(hi) effluxer CD8(+) T cells in vitro. Consequently, the CD127(low) effluxer subset may comprise cells recently exposed to IL-15. Taken together, CD127(hi) effluxer CD8(+) T cells represent a novel population of early memory T cells resident in BM with properties required for long-lived memory.

CCN1: a novel inflammation-regulated biphasic immune cell migration modulator.

In this study, we performed a comprehensive analysis of the effect of CCN1 on the migration of human immune cells. The molecule CCN1, produced by fibroblasts and endothelial cells, is considered as an important matrix protein promoting tissue repair and immune cell adhesion by binding various integrins. We recently reported that CCN1 therapy is able to suppress acute inflammation in vivo. Here, we show that CCN1 binds to various immune cells including T cells, B cells, NK cells, and monocytes. The addition of CCN1 in vitro enhances both actin polymerization and transwell migration. Prolonged incubation with CCN1, however, results in the inhibition of migration of immune cells by a mechanism that involves downregulation of PI3Kγ, p38, and Akt activation. Furthermore, we observed that immune cells themselves produce constitutively CCN1 and secretion is induced by pro-inflammatory stimuli. In line with this finding, patients suffering from acute inflammation had enhanced serum levels of CCN1. These findings extend the classical concept of CCN1 as a locally produced cell matrix adhesion molecule and suggest that CCN1 plays an important role in regulating immune cell trafficking by attracting and locally immobilizing immune cells.

Adiponectin is a negative regulator of antigen-activated T cells.

Adiponectin (APN), a cytokine constitutively produced in fat tissue, has been shown to exert anti-inflammatory effects in various disease models. While the influence of APN on monocytic cells has been extensively studied in vitro, little is known about its role in T cells. In this study, we show that while <10% of human peripheral blood T cells express adiponectin receptors (AdipoRs) on their surface, most T cells store AdipoRs in intracellular compartments. AdipoRs colocalized with immune regulatory molecules CTLA-4 and TIRC7 within clathrin-coated vesicles. After stimulation, the expression of adiponectin receptor 1 (AdipoR1) and AdipoR2 was upregulated on the surface of antigen-specific T cells, as determined by tetramer or CD137 staining, and AdipoR1 and AdipoR2 coexpressed with CTLA-4. Addition of APN resulted in a significant diminution of antigen-specific T-cell expansion. Mechanistically, APN enhanced apoptosis and inhibited proliferation of antigen-specific T-cell lines. Further, APN directly inhibited cytokine production in response to antigen stimulation. In line with the in vitro data, APN-deficient (knockout, KO) mice had higher frequencies of CD137(+) T cells upon Coxsackie B virus infection. Altogether, our data suggest that APN is a novel negative T-cell regulator. In contrast to the CTLA-4 ligand B7 only expressed on APCs, APN is abundant in human plasma.

Treatment Pathways and Health Outcomes of German Patients with Chronic Graft-Versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation: A Retrospective Health Claims Data Analysis.

BACKGROUND: Although chronic graft-versus-host-disease (cGvHD) is an important long-term complication after allogenic hematopoietic cell transplantation (allo-HCT) and is associated with increased healthcare resource utilization, real-world evidence is scarce. OBJECTIVES: The aim of the study was to evaluate survival of patients with cGvHD in Germany and to analyze hospitalization and treatment patterns. PATIENTS AND METHODS: Based on a German claims database with 4.9 million enrollees, a retrospective longitudinal analysis covering a 6-year period between 2013 and 2018 was conducted. Patients with allo-HCT in 2014 or 2015 (index date) and no record of transplantation or documentation of GvHD 365 days prior to index were included. Patients who subsequently developed a cGVHD were compared with those who did not develop a cGVHD within 3 years after index date. cGVHD cases were identified based on documented International Classification of Diseases, Tenth Revision (ICD-10) diagnosis and treatment algorithms. Since the onset of cGvHD is defined at 100 days after allo-HCT, only those alive beyond day 100 were considered in the survival analysis. Patients who did not survive the first 100 days after allo-HCT were censored to prevent a selection bias due to early mortality within patients without GvHD. Survival rates were plotted using the Kaplan-Meier estimator. The number of hospitalizations and average lengths of stay as well as treatment patterns were descriptively examined. RESULTS: Overall, 165 cGvHD patients were identified and compared with 43 patients without cGVHD. Short-term survival rates were better for patients with cGvHD; the 6-month survival probability was 95.8% for patients with cGVHD and 83.7% for patients without cGVHD. However, long-term survival was better in patients without GvHD; The 30-month survival probability was 65.5% for patients with cGVHD and 76.7% for patients without cGVHD. While overall 90% of cGvHD patients were hospitalized at least once, the share was only half for patients without GvHD (44%). 78.2% of patients with cGVHD received corticosteroids in combination with other predefined immunosuppressants. CONCLUSION: Findings from this study reveal a high disease burden associated with cGvHD. This underlines the high medical need for new interventional strategies to improve survival and morbidity after allo-HCT.

The VEGF/Rho GTPase signalling pathway: a promising target for anti-angiogenic/anti-invasion therapy.

It has become increasingly apparent that current antiangiogenic therapy elicits modest effects in clinical settings. In addition, it remains challenging to treat cancer metastasis through antiangiogenic regimes. Rho GTPases are essential for vascular endothelial growth factor (VEGF)-mediated angiogenesis and are involved in tumour cell invasion. This review discusses novel therapeutic strategies that interfere with Rho GTPase signalling and further explores this network as a target for anticancer therapy through interference with tumour angiogenesis and invasion. Recent findings describe the development of innovative Rho GTPase inhibitors. Positive clinical effects of Rho GTPase targeting in combination with conventional anticancer therapy is of increasing interest.