ReviewNew regulatory co-receptors: inducible co-stimulator and PD-1
Introduction
Activation of lymphocytes requires not only antigen presentation but also a second signal through constitutively expressed co-stimulatory receptors such as CD28 and CD40. Deficiency of CD28 and CD40 causes impaired T and B cell responses, respectively 1., 2.; however, there is a negative regulatory system for immune responses against antigens. Cytotoxic T lymphocyte antigen-4 (CTLA-4), which belongs to the CD28 family, is induced on T cells upon activation. B7-1 (CD80) and B7-2 (CD86) ligands expressed on antigen-presenting cells are shared by the positive and negative receptors (CD28 and CTLA-4, respectively). CTLA-4 delivers a negative signal to the activated T cells to downmodulate CD28-mediated positive co-stimulatory signal. Because CTLA-4 is induced by T cell activation, negative signaling by CTLA-4 is likely to be responsible for downmodulation of activated T cells. Indeed, CTLA-4-deficient mice exhibit profound lymphoproliferative phenotypes [3]. It is thus believed that the balance between stimulatory and inhibitory signaling is important to maintain tolerance and that the breakdown of self tolerance is involved in the pathogenesis of the autoimmune diseases.
Recently, a new set of the positive and negative co-receptor was identified. An inducible co-stimulator (ICOS; also known as activation-inducible lymphocyte immunomediatory molecule) expressed on activated T cells provides a positive signal by interaction with its ligand, ICOS-L (also known as B7h, GL50, B7RP-1, LICOS or B7-H2), which is constitutively expressed on B cells, macrophages and peripheral tissues 4., 5., 6., 7., 8., 9., 10., 11.. ICOS-L expression is also augmented by tumor necrosis factor α and lipopolysaccharide. PD-1 is another negative regulatory receptor induced on activated T, B and myeloid cells 12., 13., 14.. Engagement of PD-1 with its ligand PD-L1 (B7-H1) or PD-L2 (B7-DC) delivers a negative signal by recruitment of src homology 2-domain-containing tyrosine phosphatase 2 (SHP-2) to the phosphorylated tyrosine residue in the cytoplasmic region 15•., 16•., 17., 18•., 19.. C57BL/6 mice that lack PD-1 develop lupus-like arthritis and glomerulonephritis [20]. BALB/c PD-1-deficient mice develop fatal dilated cardiomyopathy with IgG deposition [21••]. Both ICOS/B7h and PD-1/PD-L1 and PD-L2 belong to the CD28/B7 family. In contrast to the B7-1 and B7-2 system, the ligands to PD-1 and ICOS are expressed not only inductively on the lymphoid system but also constitutively on parenchymal cells. The coincidence of peripheral organs that are attacked by autoimmune diseases in PD-1 deficient mice with those expressing PD-L1 and PD-L2 (heart and kidney) suggests that PD-1 may play an important role in the regulation of peripheral tolerance. This review summarizes the properties of newly identified regulatory co-receptors and their roles in maintenance of self tolerance.
Section snippets
Properties of PD-1 and its ligands
PD-1 was isolated by the subtractive-hybridization technique in 1992, as a molecule whose expression is enhanced by apoptotic stimuli [12]. PD-1 shares 21–33% amino acid sequence homology with CTLA-4/CD28/ICOS and delivers an inhibitory cosignal by engagement of PD-L1 16•., 17. or PD-L2 18•., 19.. As compared to the T-cell-restricted expression of other regulatory co-receptors, the expression of PD-1 can be induced on not only T cells but also B cells and myeloid cells, suggesting that it has
Properties of inducible co-stimulator and its ligand
ICOS was identified as a molecule that is expressed on activated T cells and has been shown to deliver stimulatory cosignal by engagement of its ligand, ICOS-L 4., 5., 6., 7., 8., 9., 10., 11.. Unlike the constitutively expressed CD28, the ICOS has to be induced on the T cell surface by antigen stimulation, which suggests that ICOS provides stimulatory cosignal to activated T cells rather than to naı̈ve T cells. The physiological significance of stimulatory cosignal to once-activated T cells is
Autoimmune diseases caused by disregulation of PD-1
As described above, comparison of timing, cell species and location of expression allow us to classify regulatory co-receptors into two pairs of stimulatory and inhibitory co-receptors: CD28/CTLA-4 and ICOS/PD-1. The activation phase of naı̈ve T lymphocytes appears to be regulated primarily by CD28/CTLA-4. By contrast, ICOS/PD-1 appears to play a role in the activation as well as effector phase of activated T and B cells. Just like the brake and accelerator of the automobile, the impairment of
Immune abnormality by disregulation of inducible co-stimulator
In contrast to PD-1, the regulation of immune tolerance by ICOS is more complex. The effect of ICOS on autoimmune diseases is best characterized using the EAE model 27•., 31.; however, the blockade of ICOS engagement can either augment or ease the EAE symptom, depending on the timing of the blockade [27•]. Inhibition of ICOS signaling at the time of antigen priming results in more severe disease and ICOS deficient mice are more susceptible to EAE; therefore, the induction of EAE does not
Conclusion
Although CD28, CTLA-4, ICOS and PD-1 have structures related to each other and probably regulate immune responses in concert, each receptor has its own indispensable role and their balance of timing, topology, magnitude or combination seems important. Any subtle unbalance can be exaggerated and lead to an inappropriate immune response, which may cause serious autoimmune diseases. Newly identified co-receptors, ICOS and PD-1, appear to be able to regulate autoreactive T and B cells in at least
Update
Dong et al. recently reported that PD-L1 (B7-H1) is highly expressed in human carcinomas, but not in normal tissues [38]. They also showed that PD-L1 expression on a tumor cell line induces apoptosis of tumor-specific T cell clones in vitro through an unknown receptor other than PD-1, which supports the growth of tumor cells in vivo.
Acknowledgements
Authors thank Yuki Shiraki for her secretarial support. This work is supported by a Center of Excellence (C.O.E.) grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Taku Okazaki and Yoshiko Iwai are graduate research and postgraduate fellows of Japan Society for the Promotion of Science (J.S.P.S.).
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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