Elsevier

Immunology Letters

Volume 196, April 2018, Pages 22-32
Immunology Letters

Invited Review
CD45 in human physiology and clinical medicine

https://doi.org/10.1016/j.imlet.2018.01.009Get rights and content

Highlights

  • CD45 regulates immune function.

  • Only few physiological ligands for human CD45 have been identified.

  • CD45 plays a role in infection, autoimmunity and cancer.

Abstract

CD45 is an evolutionary highly conserved receptor protein tyrosine phosphatase exclusively expressed on all nucleated cells of the hematopoietic system. It is characterized by the expression of several isoforms, specific to a certain cell type and the developmental or activation status of the cell. CD45 is one of the key players in the initiation of T cell receptor signaling by controlling the activation of the Src family protein-tyrosine kinases Lck and Fyn. CD45 deficiency results in T- and B-lymphocyte dysfunction in the form of severe combined immune deficiency. It also plays a significant role in autoimmune diseases and cancer as well as in infectious diseases including fungal infections. The knowledge collected on CD45 biology is rather vast, but it remains unclear whether all findings in rodent immune cells also apply to human CD45. This review focuses on human CD45 expression and function and provides an overview on its ligands and role in human pathology.

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.

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