Elisabeth Panther

T Cells with a CD4+CD25+ Regulatory Phenotype Suppress In Vitro Proliferation of Virus-Specific CD8+ T Cells during Chronic Hepatitis C Virus Infection

ABSTRACT Chronic hepatitis C virus (HCV) infection is associated with impaired proliferative, cytokine, and cytotoxic effector functions of HCV-specific CD8+ T cells that probably contribute significantly to viral persistence. Here, we investigated the potential role of T cells with a CD4+CD25+ regulatory phenotype in suppressing virus-specific CD8+ T-cell proliferation during chronic HCV infection. In vitro depletion studies and coculture experiments revealed that peptide specific proliferation as well as gamma interferon production of HCV-specific CD8+ T cells were inhibited by CD4+CD25+ T cells. This inhibition was dose dependent, required direct cell-cell contact, and was independent of interleukin-10 and transforming growth factor beta. Interestingly, the T-cell-mediated suppression in chronically HCV-infected patients was not restricted to HCV-specific CD8+ T cells but also to influenza virus-specific CD8+ T cells. Importantly, CD4+CD25+ T cells from persons recovered from HCV infection and from healthy blood donors exhibited significantly less suppressor activity. Thus, the inhibition of virus-specific CD8+ T-cell proliferation was enhanced in chronically HCV-infected patients. This was associated with a higher frequency of circulating CD4+CD25+ cells observed in this patient group. Taken together, our results suggest that chronic HCV infection leads to the expansion of CD4+CD25+ T cells that are able to suppress CD8+ T-cell responses to different viral antigens. Our results further suggest that CD4+CD25+ T cells may contribute to viral persistence in chronically HCV-infected patients and may be a target for immunotherapy of chronic hepatitis C.

Expression of the Interleukin-7 Receptor Alpha Chain (CD127) on Virus-Specific CD8+ T Cells Identifies Functionally and Phenotypically Defined Memory T Cells during Acute Resolving Hepatitis B Virus Infection

ABSTRACT Virus-specific CD8+ T cells play a central role in the outcome of several viral infections, including hepatitis B virus (HBV) infection. A key feature of virus-specific CD8+ T cells is the development of memory. The mechanisms resulting in the establishment of T-cell memory are still only poorly understood. It has been suggested that T-cell memory may depend on the survival of virus-specific CD8+ T cells in the contraction phase. Indeed, a population of effector cells that express high levels of the interleukin-7 receptor alpha chain (CD127) as the precursors of memory CD8+ T cells has recently been identified in mice. However, very little information is currently available about the kinetics of CD127 expression in an acute resolving viral infection in humans and its association with disease pathogenesis, viral load, and functional and phenotypical T-cell characteristics. To address these important issues, we analyzed the HBV-specific CD8+ T-cell response longitudinally in a cohort of six patients with acute HBV infection who spontaneously cleared the virus. We observed the emergence of CD127 expression on antigen-specific CD8+ memory T cells during the course of infection. Importantly, the up-regulation of CD127 correlated phenotypically with a loss of CD38 and PD-1 expression and acquisition of CCR7 expression: functionally with an enhanced proliferative capacity and clinically with the decline in serum alanine aminotransferase levels and viral clearance. These results suggest that the expression of CD127 is a marker for the development of functionally and phenotypically defined antigen-specific CD8+ memory T cells in cleared human viral infections.

Increased Expression of the NK Cell Receptor KLRG1 by Virus-Specific CD8 T Cells during Persistent Antigen Stimulation

ABSTRACT The killer cell lectin-like receptor G1 (KLRG1) is a natural killer cell receptor expressed by T cells that exhibit impaired proliferative capacity. Here, we determined the KLRG1 expression by virus-specific T cells. We found that repetitive and persistent antigen stimulation leads to an increase in KLRG1 expression of virus-specific CD8+ T cells in mice and that virus-specific CD8+ T cells are mostly KLRG1+ in chronic human viral infections (human immunodeficiency virus, cytomegalovirus, and Epstein-Barr virus) but not in resolved infection (influenza virus). Thus, by using KLRG1 as a T-cell marker, our results suggest that the differentiation status and function of virus-specific CD8+ T cells are directly influenced by persistent antigen stimulation.

Analysis of CD127 and KLRG1 Expression on Hepatitis C Virus-Specific CD8+ T Cells Reveals the Existence of Different Memory T-Cell Subsets in the Peripheral Blood and Liver

ABSTRACT The differentiation and functional status of virus-specific CD8+ T cells is significantly influenced by specific and ongoing antigen recognition. Importantly, the expression profiles of the interleukin-7 receptor alpha chain (CD127) and the killer cell lectin-like receptor G1 (KLRG1) have been shown to be differentially influenced by repetitive T-cell receptor interactions. Indeed, antigen-specific CD8+ T cells targeting persistent viruses (e.g., human immunodeficiency virus and Epstein-Barr virus) have been shown to have low CD127 and high KLRG1 expressions, while CD8+ T cells targeting resolved viral antigens (e.g., FLU) typically display high CD127 and low KLRG1 expressions. Here, we analyzed the surface phenotype and function of hepatitis C virus (HCV)-specific CD8+ T cells. Surprisingly, despite viral persistence, we found that a large fraction of peripheral HCV-specific CD8+ T cells were CD127+ and KLRG1− and had good proliferative capacities, thus resembling memory cells that usually develop following acute resolving infection. Intrahepatic virus-specific CD8+ T cells displayed significantly reduced levels of CD127 expression but similar levels of KLRG1 expression compared to the peripheral blood. These results extend previous studies that demonstrated central memory (CCR7+) and early-differentiated phenotypes of HCV-specific CD8+ T cells and suggest that insufficient stimulation of virus-specific CD8+ T cells by viral antigen may be responsible for this alteration in HCV-specific CD8+ T-cell differentiation during chronic HCV infection.

Selenium levels in patients with hepatitis C virus-related chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma: a pilot study.

We read with great interest the findings described by Shi et al. They detected high levels of donor-derived CD56þ, CD3þ, and CD14þ T cells in the first explanted liver grafts in both the short and long term after liver transplantation (LT). They concluded that these long-lived intragraft leukocytes in LT patients could cause long-term hematopoietic chimerism, challenging our conclusion that long-term blood chimerism is derived from hematopoietic stem/progenitor cells (HSPCs) in the liver, although they also suggest the possibility that it may result from hematopoiesis of relocated donor HSPCs. The critical issue here is whether the mature leukocytes in the intragraft are really long-lived. Natural killer (NK) cells (CD56þ) are generally considered short-lived effector cells. Although it is still controversial, recent studies have demonstrated that NK cells have the ability to become long-lived memory cells and contribute to secondary immune responses. The mechanisms for NK cell longevity are unclear, but these self-renewing capable NK cells are not just simple mature NK cell proliferation. In liver tissue, CD14þ cells are mostly Kupffer cells with a lifespan of 3.8 days, which are generated and maintained by a high monocyte influx rate or local progenitor proliferation. However, what the local progenitor cells are and where they are derived from are yet to be clarified. Based on the understanding as outlined above, we think high levels of donor-derived T cells in recipient liver are unlikely to result from a simple mature T-cell proliferation to survive for 2 years after LT. Instead, it may generate from an existent small population of donor HSPCs or blood HSPCs in liver grafts (Shi et al. appears to agree with the latter point), which are able to selfrenew and differentiation to maintain the mature leucocyte pool. In this sense, the findings by Shi et al. prove our hypothesis. Regarding the origin of HSPCs, both consistent presences in liver or from blood HSPCs are possible. We prefer the former hypothesis, because the population was maintained in liver grafts after extensive perfusion, but we did not exclude the probability of blood HSPCs in liver grafts. Finally, in 5 of the explanted liver grafts, Shi et al. could not detect donor-derived Lin CD34þ HSPCs, which does not mean the HSPCs do not exist in healthy liver grafts. That Lin CD34þ or Lin CD45þ liver cells isolated from over 30 healthy liver grafts are able to form a hematopoietic colony and engraft in immunodeficient mice are the evidence of the presence of HSPCs in liver grafts. Moreover, Lin CD34þCD38 CD90þ HSPCs only account for 0.03% of total liver cells, whereas the Lin CD34þ population described by Shi et al. was based on different human leukocyte antigen markers, which might further complicate the measurement.

Hauptursachen: Alkohol und Medikamente

ZusammenfassungLeberwerte über der Norm sind häufig. Ob sie einer weiteren Abklärung bedürfen, muss im Kontext mit der klinischen Präsentation entschieden werden. Bei asymptomatischen Personen treten Transaminasenerhöhungen meist infolge von erhöhtem Alkoholkonsum und Medikamenteneinnahmen auf.

Erhöhte Leberwerte: Was tun?

ZusammenfassungErhöhte Leberwerte sind ein häufiger Befund mit unterschiedlicher Relevanz. Die Indikation zu einer weiteren diagnostischen Abklärung hängt ab von der klinischen Präsentation sowie von Dauer und Ausmaß der Leberwerterhöhung. Dabei ist wichtig, dass auch gesunde Individuen erhöhte Leberwerte aufweisen können und dass normale Leberwerte eine Lebererkrankung nicht ausschließen [1]. Als Basisdiagnostik zur Erkennung einer Lebererkrankung eignen sich laborchemische Tests. Diese erlauben eine Aussage darüber, ob eine Leberzellschädigung (Erhöhung der Transaminasen GPT/GOT), eine Cholestase (Erhöhung von alkalischer Phosphatase, y-GT und Bilirubin) oder eine Störung der Synthesefunktion (Quick, Albumin, Cholinesterase) vorliegt. Finden sich Auffälligkeiten, die auf eine Lebererkrankung hinweisen, sollte eine weiterführende ätiologiespezifische Diagnostik veranlasst werden: zum einen, um die Ursache der Lebererkrankung zu klären und eine spezifische Therapie zu ermöglichen, zum anderen, um Aussagen zu Verlauf und Prognose der Erkrankung treffen zu können.AbstractElevated liver enzymes are a frequent clinical finding with variable significance. The indication for further diagnostic work-up depends on the clinical presentation as well as on the extent and duration of liver enzyme elevation. It is important to recognize that liver enzymes within the normal range do not exclude liver disease, while healthy individuals can present with elevated liver enzymes. Blood chemistry analyses are very valuable as screening tests for liver diseases. They allow a differentiation between liver cell damage (ALT and AST elevated), cholestasis (alkaline phosphatase, bilirubin and y-GT elevated) and liver dysfunction (prolonged INR, albumin and cholinesterase reduced). If the laboratory values indicate any signs of liver disease, further diagnostic procedures are required. These should determine the etiology of the liver disease to allow a specific treatment and in addition provide information about progress and prognosis of the disease.