The function of programmed cell death 1
and its ligands in regulating autoimmunity
Arlene H Sharpe1, E John Wherry2, Rafi Ahmed3 & Gordon J Freeman4
The programmed cell death 1 (PD-1) surface receptor binds to two ligands, PD-L1 and PD-L2. Studies have shown that PD-1–PD-L
interactions control the induction and maintenance of peripheral T cell tolerance and indicate a previously unknown function for
PD-L1 on nonhematopoietic cells in protecting tissues from autoimmune attack. PD-1 and its ligands have also been exploited by
a variety of microorganisms to attenuate antimicrobial immunity and facilitate chronic infection. Here we examine the functions
of PD-1 and its ligands in regulating antimicrobial and self-reactive T cell responses and discuss the therapeutic potential of
manipulating this pathway.
The receptor ‘programmed cell death 1’ (PD-1; also called CD279) is
inducibly expressed on CD4+ T cells, CD8+ T cells, natural killer T cells,
B cells and activated monocytes1–3. PD-1 expression is induced by T
cell receptor (TCR) or B cell receptor signaling and is augmented by
stimulation with tumor necrosis factor4. The two PD-1 ligands differ in
their expression patterns, with expression of PD-L2 being much more
restricted than PD-L1 expression1–3,5. PD-L2 (also called B7-DC and
CD273) is inducibly expressed on dendritic cells (DCs), macrophages
and cultured bone marrow–derived mast cells4. In contrast, PD-L1 (also
called B7-H1 and CD274) is expressed constitutively on murine T cells,
B cells, DCs, macrophages, mesenchymal stem cells6 and cultured bone
marrow–derived mast cells4; PD-L1 expression is further upregulated
after activation. Constitutive expression of PD-L1 is lower in humans
than in mice7. PD-L1 is also expressed on a wide variety of nonhema-
topoietic cell types, including vascular endothelial cells, epithelial cells,
muscle cells, hepatocytes, pancreatic islet cells and astrocytes in the brain,
as well as at sites of immune privilege, including the placenta and eye.
The expression of PD-L1 on nonlymphoid tissues suggests that PD-L1
may regulate self-reactive T cells or B cells and inflammatory responses
in these tissues as well as in lymphoid organs. In humans but not in
mice, PD-L2 also is expressed on vascular endothelial cells8. Interferon-
α (IFN-α), IFN-β and IFN-γ trigger upregulation of PD-L1 and, to a
lesser extent, PD-L2 expression9,10. Interleukin 4 (IL-4) and granulocyte-
macrophage colony-stimulating factor strongly stimulate the expres-
sion of PD-L2 on DCs in vitro, and IL-10 can induce the expression of
PD-L1 on monocytes11. During an active immune response, such as
acute infection or graft rejection, PD-L1 is expressed extensively on most
cells in the spleen12,13.
The PD-1 receptor is a cell surface monomer consisting of a single
immunoglobulin variable-like domain and a cytoplasmic domain
containing two tyrosine-based signaling motifs5,14. PD-1 transduces
an inhibitory signal when engaged simultaneously with the TCR or B
cell receptor but does not transduce a signal when crosslinked alone.
Phosphorylation of the second tyrosine residue, located in an immu-
noreceptor tyrosine-based switch motif, recruits the phosphatases
SHP-2 and, to a lesser extent, SHP-1 to the PD-1 cytoplasmic domain.
Recruitment of the phosphatases leads to the dephosphorylation of
effector molecules activated by TCR and B cell receptor signaling (such
as Syk and phosphatidylinositol-3-OH kinase). In addition, PD-1 signal-
ing reduces CD28-mediated activation of phosphatidylinositol-3-OH
kinase, thereby suppressing phosphorylation of the kinase Akt, glucose
metabolism and expression of the gene encoding the survival protein
Bcl-xL. The amount of PD-1 expression and the extent of engagement
of PD-1 by its ligands regulate the threshold for T cell activation and
quantities of cytokines produced.
The functions of PD-L1 and PD-L2 in T cell activation are only
beginning to be understood. Some in vitro studies suggest that PD-L1
and PD-L2 can inhibit T cell proliferation and cytokine production5,15,
whereas others indicate that PD-1 ligands enhance T cell activation16,17.
The reasons for the contradictory results of those functional stud-
ies are not yet clear but may reflect different preparations of PD-L–
immunoglobulin fusion protein acting as agonists or antagonists.
Although the existence of a second stimulatory receptor capable of
binding PD-L proteins has been postulated, it remains to be identified.
NATURE IMMUNOLOGY VOLUME 8 NUMBER 3 MARCH 2007
1Department of Pathology, Harvard Medical School and Brigham and Women’s
Hospital, Boston, Massachusetts 02115, USA. 2Immunology Program, The
Wistar Institute, Philadelphia, Pennsylvania 19104, USA. 3Emory Vaccine
Center and Department of Microbiology and Immunology, Emory University
School of Medicine, Atlanta, Georgia 30322, USA. 4Department of Medical
Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard
Medical School, Boston, Massachusetts 02115, USA.
Correspondence should be addressed to A.H.S. (email@example.com.
Received 6 December 2006; accepted 17 January 2007; published online 15
February 2007; doi:10.1038/ni1443
© 2007 Nature Publishing Group http://www.nature.com/natureimmunology
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