PD-1

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Programmed Death 1 (PD-1) is a relatively recent addition to the extended CD28/CTLA-4 family of T cell regulators[1]. PD-1 is a Type I membrane protein of 268 amino acids that is composed of an extracellular IgV domain followed by a transmembrane region and an intracellular tail. The intracellular tail contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates TCR signals[2][3]. This is consistent with binding of SHP-1 and SHP-2 phosphatases to the cytoplasmic tail of PD-1 upon ligation to its ligands. PD-1 is expressed on the surface of activated T cells, B cells, and macrophages [4],suggesting that compared to CTLA-4, PD-1 more broadly negatively regulates immune responses.

[edit] Ligands

PD-1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family[5][6]. PD-L1 protein is upregulated on macrophages and dendritic cells (DC) in response to LPS and GM-CSF treatment, and on T cells and B cells upon TCR and B cell receptor signaling, whereas in resting mice, PD-L1 mRNA can be detected in the heart, lung, thymus, spleen, and kidney[7][8]. PD-L1 is expressed on almost all murine tumor cell lines, including PA1 myeloma, P815 mastocytoma, and B16 melanoma upon treatment with IFN-γ[9][10]. PD-L2 expression is more restricted and is expressed mainly by DCs and a few tumor lines[11].

[edit] Function

Many studies indicate that PD-1 and its ligands negatively regulate immune responses. First, PD-1 knockout mice develop lupus-like glomerulonephritis and dilated cardiomyopathy on the C57BL/6 and BALB/c backgrounds, respectively[12][13]. In vitro, treatment of anti-CD3 stimulated T cells with PD-L1-Ig results in reduced T cell proliferation and IFN-γ secretion[14]. Reduced T cell proliferation correlated with attenuated IL-2 secretion, which can be rescued by addition of cross-linking anti-CD28 antibodies or exogenous IL-2[15]. Together, these data suggest that PD-1 negatively regulates T cell responses. Experiments using PD-L1 transfected DCs and PD-1 expressing transgenic (Tg) CD4 and CD8+ T cells suggest that CD8+ T cells are more susceptible to inhibition by PD-L1, although this could be dependent on the strength of TCR signaling. Consistent with a role in negatively regulating CD8+ T cell responses, using an LCMV model of chronic infection, Rafi Ahmed’s group showed that the PD-1-PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus specific CD8+ T cells, which can be reversed by blocking the PD-1-PD-L1 interaction[16].

As CTLA-4 negatively regulates anti-tumor immune responses, the closely related molecule PD-1 has been independently explored as a target for immunotherapy. The 2C TCR recognizes the peptide SIYRYYGL in the context of H 2kb. 2C CD8 T cells incubated with IFN-γ treated B16 targets expressing SIYRYYGL peptide poorly lyse their targets and secrete low levels of IL-2 [17]. However, PD-1 knockout 2C T cells have heightened cytolytic capacity and IL-2 secretion, suggesting that PD-1 negatively regulates anti-tumor CD8 T cell responses. Similarly, P815 mastocytoma, which does not express PD-L1 unless treated with IFN-γ, can be transduced to express PD-L1, resulting in inhibition of in vitro CD8-mediated cytotoxicity and enhanced in vivo tumor growth. In vitro cytotoxicity and in vivo inhibition of growth can be restored by anti-PD-L1 antibodies or by genetic ablation of PD-1[18][19]). Together, these data suggest that expression of PD-L1 on tumor cells inhibits anti-tumor activity through engagement of PD-1 on effector T cells. Expression of PD-L1 on tumors is correlated with reduced survival in esophageal, pancreatic and other types of cancers, highlighting the relevance of exploring the PD-1 pathway as a target for immunotherapy[20][21] .

[edit] References

  1. ^ Y. Ishida, Y. Agata, K. Shibahara, T. Honjo, Embo J 11, 3887 (Nov, 1992)
  2. ^ Y. Ishida, Y. Agata, K. Shibahara, T. Honjo, Embo J 11, 3887 (Nov, 1992)
  3. ^ C. Blank, A. Mackensen, Cancer Immunol Immunother 56, 739 (May, 2007)
  4. ^ Y. Agata et al., Int Immunol 8, 765 (May, 1996)
  5. ^ G. J. Freeman et al., J Exp Med 192, 1027 (Oct 2, 2000)
  6. ^ Y. Latchman et al., Nat Immunol 2, 261 (Mar, 2001)
  7. ^ G. J. Freeman et al., J Exp Med 192, 1027
  8. ^ T. Yamazaki et al., J Immunol 169, 5538 (Nov 15, 2002)
  9. ^ Y. Iwai et al., Proc Natl Acad Sci U S A 99, 12293 (Sep 17, 2002)
  10. ^ C. Blank et al., Cancer Res 64, 1140 (Feb 1, 2004)
  11. ^ Y. Latchman et al., Nat Immunol 2, 261 (Mar, 2001)
  12. ^ H. Nishimura, M. Nose, H. Hiai, N. Minato, T. Honjo, Immunity 11, 141 (Aug, 1999)
  13. ^ H. Nishimura et al., Science 291, 319 (Jan 12, 2001)
  14. ^ G. J. Freeman et al., J Exp Med 192, 1027 (Oct 2, 2000)
  15. ^ L. Carter et al., Eur J Immunol 32, 634 (Mar, 2002)
  16. ^ D. L. Barber et al., Nature 439, 682 (Feb 9, 2006)
  17. ^ C. Blank et al., Cancer Res 64, 1140 (Feb 1, 2004)
  18. ^ Y. Iwai et al., Proc Natl Acad Sci U S A 99, 12293 (Sep 17, 2002).
  19. ^ C. Blank et al., Cancer Res 64, 1140 (Feb 1, 2004).
  20. ^ Y. Ohigashi et al., Clin Cancer Res 11, 2947 (Apr 15, 2005).
  21. ^ T. Nomi et al., Clin Cancer Res 13, 2151 (Apr 1, 2007).