The receptor-like protein tyrosine phosphatase CD45 is expressed on the surface of cells of hematopoietic origin and has a pivotal role for the function of these cells in the immune response. Here we report that following infection of macrophages with mouse cytomegalovirus (MCMV) the cell surface expression of CD45 is drastically diminished. Screening of a set of MCMV deletion mutants allowed us to identify the viral gene m42 of being responsible for CD45 down-modulation. Moreover, expression of m42 independent of viral infection upon retroviral transduction of the RAW264.7 macrophage cell line led to comparable regulation of CD45 expression. In immunocompetent mice infected with an m42 deletion mutant lower viral titers were observed in all tissues examined when compared to wildtype MCMV, indicating an important role of m42 for viral replication in vivo. The m42 gene product was identified as an 18 kDa protein expressed with early kinetics and is predicted to be a tail-anchored membrane protein. Tracking of surface-resident CD45 molecules revealed that m42 induces internalization and degradation of CD45. The observation that the amounts of the E3 ubiquitin ligases Itch and Nedd4 were diminished in cells expressing m42 and that disruption of a PY motif in the N-terminal part of m42 resulted in loss of function, suggest that m42 acts as an activator or adaptor for these Nedd4-like ubiquitin ligases, which mark CD45 for lysosomal degradation. In conclusion, the down-modulation of CD45 expression in MCMV-infected myeloid cells represents a novel pathway of virus-host interaction.
Regulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruitment of TCR signalling components to the immunological synapse (IS) in www.eji-journal.euThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 2Marco van Ham et al. Eur. J. Immunol. 2017. 0: 1-16 in Treg cells, thereby, seems to be differentially organized as in Tconv cells: Treg cells show reduced Ca 2+ flux and ERK1/2 phosphorylation upon TCR stimulation [6][7][8], and downstream signalling molecules such as Lck, LAT and PLCγ1 are essential for Treg cell suppressive capacity [9,10]. In this line, a novel TCRmediated ADAP/integrin-independent PLCγ1 activation pathway was described to be required for suppression of Tconv cells by Treg cells [11]. Furthermore, Treg cells exhibit reduced S473 phosphorylation of Akt which seems a prerequisite for suppression [12]. Although the enzymatic activity of the tyrosine kinase ZAP70 seems to be dispensable for the suppressive phenotype of Foxp3 + Treg cells [13], a single mutation within the SH2-domain of ZAP70 leads to impaired suppressive activities, which indicated its importance at the immunological synapse (IS) [14]. Finally, it has only recently been recognized that the recruitment of TCR signalling components into the IS is differentially organized in Treg cells and Tconv cells. The protein kinase PKCθ is recruited to the IS in Tconv cells, in Treg cells, however, this kinase was found to be sequestered away from the IS, but still of importance to control suppression [15]. The spatial recruitment of signalling components during IS formation critically depends on cytoskeleton dynamics, which in turn is controlled by TCR activation and subsequent phosphorylation of proteins regulating cytoskeleton reorganization [5]. As part of these processes the microtubule-organizing centre (MTOC) is rapidly translocated in proximity to the IS. MTOC repositioning depends on LAT, ZAP70 and SLP76 [16] and is regulated by a cascade of distinct isoforms of the family of novel protein kinase C (nPKC) [17]. The MTOC serves as a platform to coordinate molecular movements from and to the IS through the support of microtubule (MT) motors [18]. For instance, TCR microclusters move along MTs towards the centre of the IS in a dynein-dependent manner [19], and hindrance of MTOC polarization, molecular transport and cytoskeleton dynamics prevent proper propagation of TCR signals [20].It is now tempting to speculate that the localization of signalling modules within the IS may be instrumental for the formation of a Treg cell-specific IS and the suppressive phenotype of Treg cells. At this moment, however,...
The receptor tyrosine phosphatase CD45 is expressed on the surface of almost all cells of hematopoietic origin. CD45 functions are central to the development of T cells and determine the threshold at which T and B lymphocytes can become activated. Given this pivotal role of CD45 in the immune system, it is probably not surprising that viruses interfere with the activity of CD45 in lymphocytes to dampen the immune response and that they also utilize this molecule to accomplish their replication cycle. Here we report what is known about the interaction of viral proteins with CD45. Moreover, we debate putative interactions of viruses with CD45 in myeloid cells and the resulting consequences—subjects that remain to be investigated. Finally, we summarize the evidence that pathogens were the driving force for the evolution of CD45.
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