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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    • "Indeed, these cells were strongly impaired in their ability to mediate BCR signalling upon LatA treatment (Fig EV3A–D). This observation suggests that altering the organization of CD22 may have implications for B-cell activation; however, CD45 itself plays a central role in the initiation of BCR signalling (Hermiston et al, 2003 ). Therefore , although the CD45-deficient mouse has allowed us to identify an important role for cis-interactions in the organization and dynamics of CD22 in B cells, it does not provide a straightforward model to accurately investigate the functional consequences that these interactions play in BCR signalling. "
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    ABSTRACT: Receptor organization and dynamics at the cell membrane are important factors of signal transduction regulation. Using super-resolution microscopy and single-particle tracking, we show how the negative coreceptor CD22 works with the cortical cytoskeleton in restraining BCR signalling. In naïve B cells, we found endogenous CD22 to be highly mobile and organized into nanodomains. The landscape of CD22 and its lateral diffusion were perturbed either in the absence of CD45 or when the CD22 lectin domain was mutated. To understand how a relatively low number of CD22 molecules can keep BCR signalling in check, we generated Brownian dynamic simulations and supported them with ex vivo experiments. This combined approach suggests that the inhibitory function of CD22 is influenced by its nanoscale organization and is ensured by its fast diffusion enabling a "global BCR surveillance" at the plasma membrane.
    Full-text · Article · Dec 2015 · The EMBO Journal
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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.
    Full-text · Article · Aug 2014 · BioMed Research International
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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.
    Full-text · Article · Jul 2014 · Veterinary Immunology and Immunopathology
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