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Advanced Immunology: Signaling Pathways, Transplant Rejection, and Tumor Immunology

The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumor formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors (which bind the chemical signals). Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.

Figures (10)

Key steps of the JAK-STAT pathway. JAK-STAT signalling is made of three major proteins: cell-surface receptors, Janus kinases (JAKs), and signal transducer and activator of transcription proteins (STATs). Once a ligand (red triangle) binds to the receptor, JAKs add phosphates (red circles) to the receptor. Two STAT proteins then bind to the phosphates, and then the STATs are phosphorylated by JAKs to form a dimer. The dimer enters the nucleus, binds to DNA, and causes transcription of target genes. The JAK-STAT system consists of three main components: (1) a receptor (green), which penetrates the cell membrane; (2) Janus kinase (JAK) (yellow), which is bound to the receptor, and; (3) Signal Transducer and Activator of Transcription (STAT) (blue), which carries the signal into the nucleus and DNA. The red dots are phosphates. After the cytokine binds to the receptor, JAK adds a phosphate to (phosphorylates) the receptor. This attracts the STAT proteins, which are also phosphorylated and bind to each other, forming a pair (dimer). The dimer moves into the nucleus, binds to the DNA, and causes transcription of genes. Enzymes that add phosphate groups are called protein kinases.[5]
An example of the integration between JAK-STAT, MAPK/ERK and PI3K/AKT/mTOR signalling pathways. JAKs phosphorylate cytokine receptors which can bind a protein called Grb2. Grb2 then activates SOS proteins which stimulate MAPK signalling. MAPK can also phosphorylate STATs. Phosphorylated cytokine receptors can also be bound by PI3K, which allows activation of AKT. ERK, STATs and Akt can then interact with other proteins. The receptor is not shown as a dimer, and only one side of the receptors are shown phosphorylated for simplification
Three ways PIAS proteins can inhibit JAK-STAT signaling. (A) Adding a SUMO group to STATs can block their phosphorylation, which prevents STATs entering the nucleus. (B) HDAC (histone deacetylase) recruitment can remove acetyl modifications on histones, lowering gene expression. (C) PIAS can also prevent STATs binding to DNA
Psoriasis on the hands can be caused by faulty JAK-STAT signalling.
Cytokine release via activation of JAK/STAT signalling pathway following SARS-Cov-2 infection resulting in ARDS related to COVID-19.[68]
Micrograph showing a glomerulus with changes characteristic of a transplant glomerulopathy. Transplant glomerulopathy is considered a form of chronic antibody-mediated rejection. PAS stain.
Micrographs of grades of skin graft-versus-host disease: Ranging from grade I GvHR (with minimal vacuolization in the epidermis) to grade II GvHR (with vacuolization and dyskeratotic bodies) to grade III GvHR (with sub epidermal cleft formation) and finally to grade IV GvHR (with separation of the dermis from the epidermis)[2]
GvHD pathology
cGAS bound to dsDNA. Adapted from PDB 4O6A.[10]
STING bound to cGAMP. While STING exists as a homodimer, only one subunit is shown to highlight the interaction of side chain residues with cGAMP. Adapted from PDB 4KSY[15]

Key Points

  • The JAK-STAT pathway in cytokine receptor signalling can activate STATs, which can bind to DNA and allow the transcription of genes involved in immune cell division, survival, activation and recruitment.
  • Hyperacute rejection is a form of rejection that manifests itself in the minutes to hours following transplantation.
  • Acute rejection is a category of rejection that occurs on the timescale of weeks to months, with most episodes occurring within the first 3 months to 1 year after transplantation.
  • Chronic rejection is an insidious form of rejection that leads to graft destruction over months to years after tissue transplantation.
  • Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs.
  • Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue.

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