Programmed cell death 1 ligand 2 (also known as PD-L2, B7-DC) is a protein that in humans is encoded by the PDCD1LG2 gene. [5] [6] PDCD1LG2 has also been designated as CD273 (cluster of differentiation 273). PDCD1LG2 is an immune checkpoint receptor ligand which plays a role in negative regulation of the adaptive immune response. [5] [7] PD-L2 is one of two known ligands for Programmed cell death protein 1 (PD-1). [5]
PD-L2 is a cell surface receptor belonging to the B7 protein family. [8] It consists of both an immunoglobulin-like variable domain and an immunoglobulin-like constant domain in the extracellular region, a transmembrane domain, and a cytoplasmic domain. [8] PD-L2 shares considerable sequence homology with other B7 proteins, [9] but it does not contain the putative binding sequence for CD28/CTLA4, namely SQDXXXELY or XXXYXXRT. [9]
The crystal structure of murine PD-L2 bound to murine PD-1 has been determined. [10] as well as the structure of the hPD-L2/mutant hPD-1 complex. [11]
PD-L2 is primarily expressed on professional antigen presenting cells including dendritic cells (DCs) and macrophages. [12] Others have shown PD-L2 expression in certain T helper cell subsets and cytotoxic T cells. [13] [14] PD-L2 protein is widely expressed in many healthy tissues including the GI tract tissues, skeletal muscles, tonsils, and pancreas. [15] Additionally, PD-L2 has moderate to high expression in triple-negative breast cancer and gastric cancer and low expression in renal cell carcinoma. [16] PD-L2 mRNA is widely expressed and not enriched in any particular tissue. [15]
Interleukin-4 (IL-4) and granulocyte-macrophage colony stimulating factor (GMCSF) both upregulate PD-L2 expression in DCs in vitro . [12] IFN-α, IFN-β, and IFN-γ induce moderate upregulation of PD-L2 expression. [12]
PD-L2 binds to its receptor PD-1 with dissociation constant Kd of 11.3 nM. [17] Binding to PD-1 can activate pathways inhibiting TCR/BCR-mediated immune cell activation [12] (for a more detailed discussion see PD-1 signaling). PD-L2 plays an important role in immune tolerance and autoimmunity. [18] Both PD-L1 and PD-L2 can inhibit T cell proliferation and inflammatory cytokine production. [17] Blocking PD-L2 has been shown to exacerbate experimental autoimmune encephalomyelitis. [18] Unlike PD-L1, PD-L2 has been shown activate the immune system. PD-L2 triggers IL-12 production in murine dendritic cells leading to T cell activation. [17] Others have shown that treatment with PD-L2 Ig led to T helper cell proliferation. [18]
PD-L2, PD-L1, and PD-1 expressions are important in the immune response to certain cancers. Due to their role in suppressing the adaptive immune system, efforts have been made to block PD-1 and PD-L1, resulting in FDA approved inhibitors for both (see pembrolizumab, nivolumab, atezolizumab). There are still no FDA approved inhibitors for PD-L2 as of 2019. [19]
The direct role of PD-L2 in cancer progression and immune-tumor microenvironment regulation is not as well studied as the role of PD-L1. [16] In mouse cell cultures, PD-L2 expression on tumor cells suppressed cytotoxic T cell-mediated immune responses. [20]
Indirectly, PD-L2 may have utility as a biomarker or prognostic indicator. PD-L2 expression has been shown to predict response to PD-1 blockade with pembrolizumab independently of PD-L1 expression. [16] However, PD-L2 does not putatively predict outcome in cancer, with some studies suggesting it predicts negative prognoses [21] [22] [23] and other studies suggesting it predicts positive prognoses. [24]
Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.
An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T-cells.
Cytotoxic T-lymphocyte associated protein 4, (CTLA-4) also known as CD152, is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation – a phenomenon which is particularly notable in cancers. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells. It is encoded by the gene CTLA4 in humans.
Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.
The Cluster of differentiation 80 is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is closely related to CD86, another B7 protein (B7-2), and often works in tandem. Both CD80 and CD86 interact with costimulatory receptors CD28, CTLA-4 (CD152) and the p75 neurotrophin receptor.
Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.
Cancer immunology (immuno-oncology) is an interdisciplinary branch of biology and a sub-discipline of immunology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.
C-C chemokine receptor type 7 is a protein that in humans is encoded by the CCR7 gene. Two ligands have been identified for this receptor: the chemokines ligand 19 (CCL19/ELC) and ligand 21 (CCL21). The ligands have similar affinity for the receptor, though CCL19 has been shown to induce internalisation of CCR7 and desensitisation of the cell to CCL19/CCL21 signals. CCR7 is a transmembrane protein with 7 transmembrane domains, which is coupled with heterotrimeric G proteins, which transduce the signal downstream through various signalling cascades. The main function of the receptor is to guide immune cells to immune organs by detecting specific chemokines, which these tissues secrete.
Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.
Programmed cell death protein 1(PD-1),. PD-1 is a protein encoded in humans by the PDCD1 gene. PD-1 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.
ICOS ligand is a protein that in humans is encoded by the ICOSLG gene located at chromosome 21. ICOSLG has also been designated as CD275.
Natural cytotoxicity triggering receptor 3 is a protein that in humans is encoded by the NCR3 gene. NCR3 has also been designated as CD337 and as NKp30. NCR3 belongs to the family of NCR membrane receptors together with NCR1 (NKp46) and NCR2 (NKp44).
Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biologic effects on T cell function. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.
Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3)gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells. HAVCR2 receptor is a regulator of the immune response.
Macrophage receptor with collagenous structure (MARCO) is a protein that in humans is encoded by the MARCO gene. MARCO is a class A scavenger receptor that is found on particular subsets of macrophages. Scavenger receptors are pattern recognition receptors (PRRs) found most commonly on immune cells. Their defining feature is that they bind to polyanions and modified forms of a type of cholesterol called low-density lipoprotein (LDL). MARCO is able to bind and phagocytose these ligands and pathogen-associated molecular patterns (PAMPs), leading to the clearance of pathogens and cell signaling events that lead to inflammation. As part of the innate immune system, MARCO clears, or scavenges, pathogens, which leads to inflammatory responses. The scavenger receptor cysteine-rich (SRCR) domain at the end of the extracellular side of MARCO binds ligands to activate the subsequent immune responses. MARCO expression on macrophages has been associated with tumor development and also with Alzheimer's disease, via decreased responses of cells when ligands bind to MARCO.
Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.
PD-1 inhibitors and PD-L1 inhibitors are a group of checkpoint inhibitor anticancer drugs that block the activity of PD-1 and PDL1 immune checkpoint proteins present on the surface of cells. Immune checkpoint inhibitors are emerging as a front-line treatment for several types of cancer.
V-domain Ig suppressor of T cell activation (VISTA) is a type I transmembrane protein that functions as an immune checkpoint and is encoded by the C10orf54 gene.
Tolerogenic dendritic cells are heterogenous pool of dendritic cells with immuno-suppressive properties, priming immune system into tolerogenic state against various antigens. These tolerogenic effects are mostly mediated through regulation of T cells such as inducing T cell anergy, T cell apoptosis and induction of Tregs. Tol-DCs also affect local micro-environment toward tolerogenic state by producing anti-inflammatory cytokines.
CD28 family receptors are a group of regulatory cell surface receptors expressed on immune cells. The CD28 family in turn is a subgroup of the immunoglobulin superfamily.
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