Invited ReviewCD45 in human physiology and clinical medicine
Introduction
CD45 is a central player of immune cell activation. The huge amount of data contributing to our understanding of CD45 biology is based on experiments using either human blood samples, human cell lines (Jurkat cells) or non-human sources (mainly rodents). Whether all findings on murine CD45 also apply to human physiology remains unclear as differences in T cell physiology of humans and mice have been reported including differences between human and mouse CD45 molecules [[1], [2]], which are distinguished by certain pathogens [3]. The dispersion of the various CD45 isoforms also differs between species: in mice, B220 is a pan-B cell-specific CD45 isoform while this particular isoform is developmentally regulated in humans and downregulated upon acquisition of CD27, a memory B cell-marker [4]{h}. There are a number of excellent reviews covering a variety of issues of CD45 biology. This review aims to focus on CD45's role in human physiology and clinical pathology. Literature based on experiments using human material is indicated by {h} directly after the quotation.
Section snippets
CD45 expression and CD45 isoforms
CD45 is a receptor protein tyrosine phosphatase, also known as Ly-5 [5] or leukocyte common antigen [6]{h}. CD45 is expressed on the surface of all nucleated hematopoietic cells and their precursors, except mature erythrocytes and platelets. It is a large glycoprotein of 180–220 kDa and constitutes 5–10% of the total glycoprotein on the surface of T- and B-lymphocytes [[7], [8]]. CD45 expression is not limited to mammals, as there are CD45 homoloques in chicken, shark and even mosquitos [9], an
CD45 function and regulation
When T cells encounter cognate antigen presented on MHC molecules of antigen presenting cells (APCs) they form long-lasting cell conjugates and build an immunological synapse (IS) in the T cell-APC contact zone, which is essential for T-cell activation. In the IS, CD45 and Lck are initially recruited to the central supramolecular activation cluster (cSMAC) via the TCR. CD45 is then expelled from the cSMAC and clusters in the distal SMAC (dSMAC) [[40], [41], [42], [43], [44]]. One model, the
CD45 and its natural ligands
For a long time, it has been unclear whether there is any natural CD45 ligand at all. There is a variety of artificially created extracellular ligands, but this review will only focus on natural extracellular CD45 ligands. A number of CD45 ligands has been identified, but most of them are not binding exclusively to CD45. Some of the ligands are only present under certain clinical conditions like an ongoing infection or in pregnancy and there seems to be no natural extracellular ligand that can
CD45 and lectins
Another group of ligands binding CD45 are lectins. They are hardly exclusive CD45 binding partners as they are ubiquitously expressed and are known to interact with a large variety of molecules. One of the lectins binding CD45 is CD22, a B cell surface molecule belonging to the SIGLEC family of lectins [144]. CD22 exerts an inhibitory effect on basal B cell receptor (BCR) signaling. CD45 restricts the inhibitory function of CD22 in a phosphatase independent manner, presumably by sequestering
Viral infections
To get a foothold in its hosts, a virus has to modulate the host immune response [163]. CD45, as a major player in the immune response of T and B cells, obviously is a suitable target. It has been mentioned before that one protein targeting CD45, probably exclusively, is pUL11 [3]{h}. A protein sharing some characteristics with pUL11 is E3/49 K of adenovirus (AdV) type 19a, which, in its soluble form, binds to CD45 [164]{h}. The secreted version of the ectodomain of E3/49 K, sec49 K, seems to
CD45 as a therapeutic target
CD45, being an important regulator of immune cell signaling pathways, has been linked to several diseases [[207], [208]] and thus, therapeutic modulation of CD45 function has direct clinical applicability in organ transplantation, treatment of autoimmune disease or microglial activation associated with Alzheimer disease (AD). As a matter of fact, CD45 was one of the first protein tyrosine phosphatases to be considered as a drug target. To modulate CD45 function, selective phosphatase inhibitors
Conclusions and perspectives
CD45 was identified about three decades ago and has turned out to be a key player in the regulation and modulation of the immune response. However, it seems that the more details emerge about CD45, the more questions arise. One of the key questions was and still is the search for physiological ligands. Apparently exclusive binding partners currently known are pUL11, PP14 and E3/49 K. All of them seem to have no other binding partners than CD45. A variety of lectins also bind to CD45, but to a
Conflict of interest
None.
Funding
This work was supported by grants from the German Research Society (CRC854, B19) and the State of Saxony-Anhalt (SI2) to B.S.
Acknowlegement
We apologize that not all of the excellent work on CD45 could be cited. The authors thank Martin Voss for graphical artwork.
References (236)
- et al.
Human T cell activation results in extracellular signal-regulated kinase (ERK)-calcineurin-dependent exposure of Tn antigen on the cell surface and binding of the macrophage galactose-type lectin (MGL)
J. Biol. Chem.
(2013) - et al.
The ST6 Gal I sialyltransferase selectively modifies N-glycans on CD45 to negatively regulate galectin-1-induced CD45 clustering, phosphatase modulation, and T cell death
J. Biol. Chem.
(2003) - et al.
The leukocyte common antigen, CD45 and other protein tyrosine phosphatases in hematopoietic cells
Semin. Cell Biol.
(1993) - et al.
A C-type lectin collaborates with a CD45 phosphatase homolog to facilitate West Nile virus infection of mosquitoes
Cell
(2010) - et al.
Peripheral blood fibrocytes from burn patients: identification and quantification of fibrocytes in adherent cells cultured from peripheral blood mononuclear cells
Lab. Investig. J. Tech. Methods Pathol.
(2002) - et al.
A unique human blood-derived cell population displays high potential for producing insulin
Biochem. Biophys. Res. Commun.
(2007) - et al.
CD45 isoforms in T cell signalling and development
Immunol. Lett.
(2004) - et al.
Differential costimulation through CD137 (4-1BB) restores proliferation of human virus-specific effector memory (CD28(−) CD45RA(HI)) CD8(+) T cells
Blood
(2007) - et al.
Properties of end-stage human T cells defined by CD45RA re-expression
Curr. Opin. Immunol.
(2012) - et al.
Cell generation within human thymic subsets defined by selective expression of CD45 (T200) isoforms
Hum. Immunol.
(1990)