Boster Pathways-> Immunology and Inflammation

Immune Checkpoint Signaling Pathway

The inbuilt control mechanisms of the immune system that maintain self - tolerance and help avoid collateral damage during physiological immune response.

Overview of Immune Checkpoint Signaling Pathway

In the immunological checkpoint signaling system, there are two types of checkpoint molecules. One is to stimulate the immune system, while the other is to suppress it. They are cell surface receptors that bind to ligands released by other cells and trigger changes in cell activity. Through the observation of animal defect model phenotypes, the researchers were able to classify these immune checkpoint molecules.

These pathways are critical for self tolerance which prevents the immune system from attacking cells indiscriminately. Immune checkpoints play a key role in maintaining immune homeostasis and preventing autoimmunity. Therefore an immune response is tightly regulated and multiple mechanisms are in place to prevent autoimmune reactions to self proteins. These mechanisms are implemented by immune checkpoint molecules which include cytotoxic T lymphocyte antigen - 4,programmed death - 1, lymphocyte activation gene - 3,T - cell immunoglobutin and mucin protein - 3. Checkpoint molecules play a critical role in objective tumor responses and improved overall survival. There are different and many scientists who have been involved in the study of the immune checkpoints. Some include Duncan w, Croft M, Joroosh P (2009)discovered and studied the significance of Ox40 and Ox40L to T-cell biology and immune diseases. Angamatsa K. (2000)studied and did an extensive research on memory B cells and CD27.

History of Immune Checkpoint Signaling Pathway

There are different and many scientists who have been involved in the study of the immune checkpoints. Some include Duncan w, Croft M, Joroosh P (2009) discovered and studied the significance of Ox40 and Ox40L to T-cell biology and immune diseases. Angamatsa K. (2000) studied and did an extensive research on memory B cells and CD27.

Stimulatory checkpoint molecules

There are eight molecules that operate as activation checkpoints. CD27, CD40, OX40, GITR, and CD137 are members of the tumor necrosis factor (TNF) receptor superfamily, which includes four stimulatory checkpoint molecules. The B7-CD28 superfamily also includes CD28 and ICOS, which are also stimulatory checkpoint molecules.

Activation Checkpoint Molecules

CD27 - This molecule promotes antigen-specific growth of naive T cells and is required for T cell memory formation. It's also a B-cell memory marker. The temporary availability of its ligand, CD70, on lymphocytes and dendritic cells, controls its activity.

CD28 is a molecule that is expressed on nearly all human CD4+ T cells and around half of all CD8 T cells. T cell expansion is triggered by binding with its two ligands, CD80 and CD86, which are expressed on dendritic cells. TGN1412 was found to be a target of CD28, which resulted in severe inflammatory reactions.

CD40L, also known as CD154 and transiently expressed on the surface of activated CD4+ T cells, is the ligand for this molecule, which is located on a number of immune system cells including antigen presentation cells. Dendritic cells are known to be 'licensed' to mature by CD40 signaling, which then triggers T-cell activation and differentiation.

CD122 - This protein, which is the beta subunit of the Interleukin-2 receptor, is known to promote the proliferation of CD8+ effector T cells.

CD137 - T-cell proliferation occurs when this molecule, also known as 4-1BB, is bound by CD137 ligand. T lymphocytes, particularly CD8+ T cells, are known to be protected against activation-induced cell death by CD137-mediated signaling.

OX40 - The ligand for this molecule, also known as CD134, is OX40L, or CD252. OX40, like CD27, supports the proliferation of effector and memory T cells, but it's also known for suppressing T-regulatory cell differentiation and activity, as well as regulating cytokine production.

GITR, or Glucocorticoid-Induced TNFR Family Related Gene, is a gene that causes T cell expansion, particularly regulatory T cell expansion. The GITR ligand is mostly found on antigen-presenting cells.

ICOS - Inducible T-cell costimulator, also known as CD278, is a molecule that is expressed on activated T cells. Its ligand, ICOSL, is mostly expressed on B cells and dendritic cells. The molecule appears to play a role in the function of T cell effectors.

Inhibitory checkpoint molecules

Immune checkpoint inhibitors have gotten increasing attention and research as a result of their better performance in the treatment of malignancies.

Inhibition checkpoint molecules

Because adenosine in the immune milieu, which activates the A2a receptor, is a negative immunological feedback loop, and the tumor microenvironment has relatively high adenosine concentrations, the Adenosine A2A receptor is viewed as a key checkpoint in cancer therapy.

B7-H3, also known as CD276, was once thought to be a co-stimulatory molecule, but is now thought to be co-inhibitory.

B7-H4, also known as VTCN1, is a protein expressed by tumor cells and tumor-associated macrophages that aids tumor escape.

HVEM (Herpesvirus Entry Mediator) is the ligand for BTLA (B and T Lymphocyte Attenuator), which is also known as CD272. The expression of BTLA on the surface of human CD8+ T cells decreases as they progress from naïve to effector cell phenotype, whereas tumor-specific human CD8+ T cells express high amounts of BTLA.

CTLA-4 is also known as CD152 and stands for Cytotoxic T-Lymphocyte-Associated Protein 4. CTLA-4 expression on regulatory T cells regulates T cell proliferation.

IDO, or Indoleamine 2, 3-dioxygenase, is a tryptophan catabolic enzyme that inhibits the immune system. IDO suppresses T and NK cells, generates and activates regulatory T cells and myeloid-derived suppressor cells, and promotes tumor angiogenesis, among other things.

Killer-cell is abbreviated as KIR. On Natural Killer cells, the Immunoglobulin-like Receptor is a receptor for MHC Class I molecules.

LAG3 stands for Lymphocyte Activation Gene 3. Gene-3 suppresses the immunological response by acting on regulatory T cells as well as CD8+ T cells directly.

The PD-1 receptor has two ligands, PD-L1 and PD-L2, and is short for Programmed Death 1 (PD-1). Targeting PD-1 has the added benefit of restoring immune activity in the tumor microenvironment.

T-cell Immunoglobulin Domain and Mucin Domain 3 (TIM-3) is a protein that regulates Th1 and Th17 cytokines in activated human CD4+ T cells. When TIM-3 interacts with its receptor, galectin-9, it causes cell death, acting as a negative regulator of Th1/Tc1 activity.

VISTA (protein) - VISTA stands for V-domain Ig suppressor of T cell activation. Because VISTA is largely expressed on hematopoietic cells, consistent expression of VISTA on leukocytes within tumors may allow VISTA blockage to be effective across a wide spectrum of solid tumors.