Review
The PD-1/PD-Ls pathway and autoimmune diseases

https://doi.org/10.1016/j.cellimm.2014.05.006Get rights and content

Highlights

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    We give a review about the soluble forms of PD-1/PD-Ls pathway.

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    We give a summary figure about the function of sPD-1.

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    We give a summary figure about the role of PD-1/PD-Ls pathway in T1DM.

Abstract

The programmed death (PD)-1/PD-1 ligands (PD-Ls) pathway, is a new member of the B7/CD28 family, and consists of the PD-1 receptor and its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273). Recently, it is reported that PD-1, PD-L1 and PD-L2 also have soluble forms aside from their membrane bound forms. The soluble forms increase the diversity and complexity of PD-1/PD-Ls pathway in both composition and function. The PD-1/PD-Ls pathway is broadly expressed and exerts a wider range of immunoregulatory roles in T-cell activation and tolerance compared with other B7/CD28 family members. Studies show that the PD-1/PD-Ls pathway regulates the induction and maintenance of peripheral tolerance and protects tissues from autoimmune attack in physiological conditions. In addition, it is also involved in various diseases mediated by T cells, such as autoimmunity, tumor immunity, chronic viral infections, and transplantation immunity. In this review, we will summarize the relevance of the soluble forms and the latest researches on the role of PD-1/PD-Ls pathway in autoimmune diseases.

Section snippets

Structure and expression of PD-1

Programmed death-1 (PD-1) is a 50 ∼ 55-kDa type I transmembrane glycoprotein composed of an IgV-type extracellular domain sharing 21 ∼ 33% sequence identity with cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), CD28 and inducible co-stimulatory molecule (ICOS). Unlike CTLA-4 that forms homodimer, PD-1 lacks the membrane proximal cysteine residue required for homodimerization and is supposed to exist as monomer on the cell surface as well as in solution. Meanwhile, PD-1 lacks the proline-rich

The mechanism of PD-1/PD-Ls signaling

PD-1 ligation, along with B-cell receptor (BCR) signaling, results in phosphorylation of the cytoplasmicdomaintyrosines and recruitment of SHP-2(SRC Homology 2-Domain-Containingprotein Tyrosine Phosphatase 2). Then SHP-2 dephosphorylates BCR-proximal signaling molecules including Igα/β and Syk, which attenuates the activation of downstream molecules including PLCγ2, PI3K, vav, and ERK1/2. PD-1 inhibits T-cell receptor (TCR) signaling by similar mechanisms. PD-1 ligation, along with TCR

The production of sPD-1, sPD-L1 and sPD-L2

Many co-stimulatory molecules assume two forms of expression. Aside from their membrane bound forms, soluble forms have been found for several members of B7 superfamily such as B7-1, B7-2 and B7-H3. The soluble proteins can play important roles in the regulation of co-stimulatory signals. Soluble forms of receptors or ligands are generally produced through proteolytic cleavage of membrane bound proteins such as the soluble tumor necrosis factor (sTNF) and sB7-H3, or by translation of

The function of sPD-1 and sPD-L1

sPD-1, sPD-L1 and sPD-L2 increase the diversity and complexity of PD-1/PD-Ls pathway in both composition and function. However, the role of sPD-1 and sPD-L1 in the regulation of PD-1/PD-Ls pathway is still under debate and so far, there is no report about the biological function of sPD-L2.

Biological significance of PD-1/PD-Ls pathway

In this section, we will review the latest researches on the role of PD-1/PD-Ls pathway in autoimmune diseases.

Conclusions

The PD-1/PD-Ls pathway is a key regulator in T-cell activation and tolerance followed by induction and maintenance of peripheral tolerance. Currently, it is clear that PD-1/PD-Ls pathway plays crucial roles in autoimmunity, transplantation immunity, infectious immunity, and tumor immunity. The biological significance sheds light on the development of therapeutic strategies against these diseases by manipulating the PD-1/PD-Ls pathway with antagonists or agonist. Nevertheless, the PD-1/PD-Ls

Acknowledgments

This work was supported by the National Nature Science Foundation of China (No 81371880).

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