CD45: A Critical Regulator of Signaling Thresholds in Immune Cells

Department of Pediatrics, University of California, San Francisco, 94143, USA.
Annual Review of Immunology (Impact Factor: 39.33). 02/2003; 21(1):107-37. DOI: 10.1146/annurev.immunol.21.120601.140946
Source: PubMed


Regulation of tyrosine phosphorylation is a critical control point for integration of environmental signals into cellular responses. This regulation is mediated by the reciprocal actions of protein tyrosine kinases and phosphatases. CD45, the first and prototypic receptor-like protein tyrosine phosphatase, is expressed on all nucleated hematopoietic cells and plays a central role in this process. Studies of CD45 mutant cell lines, CD45-deficient mice, and CD45-deficient humans initially demonstrated the essential role of CD45 in antigen receptor signal transduction and lymphocyte development. It is now known that CD45 also modulates signals emanating from integrin and cytokine receptors. Recent work has focused on regulation of CD45 expression and alternative splicing, isoform-specific differences in signal transduction, and regulation of phosphatase activity. From these studies, a model is emerging in which CD45 affects cellular responses by controlling the relative threshold of sensitivity to external stimuli. Perturbation of this function may contribute to autoimmunity, immunodeficiency, and malignancy. Moreover, recent advances suggest that modulation of CD45 function can have therapeutic benefit in many disease states.

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    • "CD45 is essentialin T-cell differentiation and antigen receptor signaling [64]. When inflammatory agents activate noneffector CD45RA+CD45RO− T lymphocytes, such as bacterial infection, the isoform CD45RO is upregulated and CD45RA is downregulated [65]. CD28 is a costimulatory molecule that plays a key role in regulating the activation and surviving of T lymphocytes [66–68]. "
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    ABSTRACT: Sepsis is a systemic inflammatory response syndrome due to infection. The incidence rate is estimated to be up to 19 million cases worldwide per year and the number of cases is rising. Infection triggers a complex and prolonged host response, in which both the innate and adaptive immune response are involved. The disturbance of immune system cells plays a key role in the induction of abnormal levels of immunoregulatory molecules. Furthermore, the involvement of effector immune system cells also impairs the host response to the infective agents and tissue damage. Recently, postmortem studies of patients who died of sepsis have provided important insights into why septic patients die and showed an extensive depletion of CD4 and CD8 lymphocytes and they found that circulating blood cells showed similar findings. Thus, the knowledge of the characterization of circulating lymphocyte abnormalities is relevant for the understanding of the sepsis pathophysiology. In addition, monitoring the immune response in sepsis, including circulating lymphocyte subsets count, appears to be potential biomarker for predicting the clinical outcome of the patient. This paper analyzes the lymphocyte involvement and dysfunction found in patients with sepsis and new opportunities to prevent sepsis and guide therapeutic intervention have been revealed.
    BioMed Research International 08/2014; 2014:671087. DOI:10.1155/2014/671087 · 2.71 Impact Factor
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    • "CD45 is frequently used as a cell surface marker for pan-leukocyte (all isotypes of CD45), B lymphocyte (high molecular isoform of CD45; i.e. B220) (Johnson et al., 1989), naïve T lymphocyte (high molecular weight isoform of CD45; CD45RA or CD45RB) and memory T lymphocyte (low molecular weight isoform of CD45; CD45RO) (Birkeland et al., 1989; Croft et al., 1994; Hermiston et al., 2003) in humans and mice. It can be predicted that the expression pattern of multiple isoforms of CD45 is similar in canine as well, but no study has been carried out so far. "
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    ABSTRACT: CD45 is one of the most abundant molecules expressed on the white blood cell surface in various mammals. In this study, we investigated the differential expression of CD45 isoforms in normal canine white blood cells. It has been shown that all canine nucleated blood cells express CD45. We characterized 2 major isoforms of canine CD45 derived from alternative splicing: a higher molecular weight isoform, CD45RA, and a lower molecular weight isoform, CD45RO. The nucleotide sequences of the 2 isoforms were identical, except for the region corresponding to a part in the extracellular domain. Flow cytometry analysis using an antibody that recognizes CD45RA, but not CD45RO, revealed that granulocytes did not express CD45RA, and monocytes express low levels of CD45RA. We further analyzed the expression levels of CD45RA in each lymphocyte subpopulation and found that the expression of CD45RA on CD21+ B cells was uniform. On the other hand, expression of CD45RA on CD3+ T cells was variable. Upon stimulation of lymphocytes with Con A, the CD45RA+ fraction increased, indicating that not only the phenotypes but also the activation status influences the isoform expression pattern of CD45. Our finding provides a basic knowledge of the expression of canine CD45, which could be a tool to study lymphocytes with various phenotypes, developmental stages, and activation status.
    Veterinary Immunology and Immunopathology 07/2014; 160(1-2). DOI:10.1016/j.vetimm.2014.03.011 · 1.54 Impact Factor
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    • "The M1 subtype overproduces pro-inflammatory cytokines and promotes cell-mediated immunity, whereas M2 microglia tends to dampen inflammation and clear cellular debris [29]. In this context CD45, a hematopoietic cell-specific protein tyrosine phosphatase, acts as a negative regulator of cytokine receptor signaling leading to altered microglial activation [29-31]. We observed that JEV infection in miR-155 overexpressing human microglial cells up-regulated CD45 expression on cell surface (Figure 6A). "
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    ABSTRACT: Background Microglial cells, which are resident macrophages of the central nervous system, play important roles in immune responses and pathogenesis. Japanese encephalitis virus (JEV) is a neurotropic virus that infects microglial cells in brain. Several microRNAs including miR-155 and miR-146a play an important role in defining the microglia inflammatory profile. In this study, we have investigated the effect of miR-155 and miR-146a modulation on JEV infection as well as innate immune responses in human microglial cells. Methods In vitro studies were performed in JEV-infected human microglial CHME3 cells. miR-155 or miR-146a were overexpressed and total RNA and protein were extracted following JEV-infection. Expression of genes involved in innate immune responses was studied by PCR array, quantitative real-time PCR (qPCR), western blot and Fluorescence activated cell sorter (FACS). JEV replication was monitored by studying the viral RNA by qPCR, protein by western blot, and titres by plaque assay. Results Overexpression of miR-155 in CHME3 cells resulted in significantly reduced JEV replication whereas miR-146a overexpression had an insignificant effect. Additionally, interferon regulatory factor 8 (IRF8) and complement factor H (CFH) were induced during JEV infection; however, this induction was attenuated in miR-155 overexpressing cells following JEV infection. Further, JEV-induced NF-κB regulated downstream gene expression was attenuated. Interestingly, an increased level of CD45, a negative regulator of microglia activation and a reduced phosphorylated-Signal Transducers and Activators of Transcription (p-STAT1) expression was observed in miR-155 overexpressing cells upon JEV infection. Conclusion Induction of miR-155 in human microglial cells may negatively modulate JEV-induced innate immune gene expression and may have a beneficial role in limiting JEV replication in human microglial cells.
    Journal of Neuroinflammation 05/2014; 11(1):97. DOI:10.1186/1742-2094-11-97 · 5.41 Impact Factor
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