Cellular signaling – immune system communication


image_pdfimage_print

Communication within the human body

Communication within the body can take one of three different forms:

Autocrine signaling
A form of signaling where cells can communicate with themselves. In this pathway, the cell directly affects its own function by secreting substances which can act on the cellular receptors.

Paracrine signaling
Cells can also communicate with cells in the immediate environment. Paracrine signaling is especially important in the local immune response.

Endocrine signaling
Signaling at a distance. Occurs through the presence of hormones. Hormones are biologically active substances which are secreted into the bloodstream. Many of the regulators of white cell growth and development, for example, are hormones.

Effects of signaling molecules

cellular signalingSignaling molecules usually have an effect within the cell by affecting gene transcription. This in turn alters the proteins which are made by that cell which can have a structural or a functional effect. Interleukin 2, for example, is a cell signal which is secreted by activated T lymphocytes and results in increased transcription of genes coding for the HLA molecules in macrophages – macrophages then become more adept at presenting antigen to the T cells resulting in an enhanced immune response.

Small nuclear receptors

Small nuclear receptors are often lipid molecules. For this reason, they can diffuse directly across the lipid bilayer of the cell membrane and the nuclear membrane. In the nucleus, they can bind directly to the DNA material and enhance expression. In the immune response, two important molecules are corticosteroid agents and vitamin D, both results in an immunosuppressive response.

Cell signaling receptors

Most cell signaling molecules are proteins which must bind to specialised receptors on the surface of cell membranes. These receptors take many forms, often relying on downstream signaling molecules which can either act as second messengers to transmit the message or modify the signal by amplifying it, changing it to another form, splitting it or combining it with other signals. The involvement of these downstream signaling molecules results in a cascade. Two important molecules involved in downstream signaling are intracellular calcium and the small protein molecule, Ras.

Ras or rat associated sarcoma was first discovered as an important molecule in rat malignancy. It binds to the internal surface of plasma membrane. It is activated by binding the high energy compound guanidine triphosphate (GTP) and is inactive if guanidine diphosphate is bound. It is known as a small G protein because it is activated by this mechanism. The enzymes responsible for catalysing the conversion of GDP to GTP are known as guanine-nucleotide exchange factors (GEFs).

Calcium is a divalent cation which, in resting cells, is stored within membranous organelles (especially the mitochondrion). If the cell is activated, calcium is released resulting in downstream signaling. It is important that the calcium influx is regulated and terminated. Calcium is bound to calmodulin in the cell and pumps act quickly when calcium is released to return it to the organelles.

G protein-associated receptors

figure 2 figure 1G protein-associated receptors are also called serpentine receptors because they consist of a protein molecule which passes through the cell membrane seven times. G protein receptors are ubiquitous in the human body. Some important examples include the olfactory receptors and the rods and cones which are responsible for vision. In the immune system, G protein receptors are important as chemokine receptors (e.g. CCR5).

G protein receptors are linked to a molecule which is bound on the internal surface of the cell membrane. This molecule consists of three parts – α, β, and γ subunits and is inactive when bound to GDP. On activation of the G protein-linked receptor, GDP is phosphorylated to GTP which enables the α subunit to dissociate from the βγ subunit. The α subunit has an intrinsic GTPase activity and rapidly terminates the activation of the receptor. This has downstream effects including activation of the enzyme phospholipase C or phospholipase A and activation of adenylate cyclase.

Phospholipase C acts on the lipid membrane and breaks down the phospholipids into inositol triphosphate (IP3) and diacylglyceral (DAG). IP3 acts to release calcium from stores which increases metabolic rate, secretion of fluids and enzymes and activates cell proliferation. In the immune system, one of the key functions of calcium is to activate the enzyme calcineurin which, in turn, activates the pro-inflammatory NFAT system. DAG activates protein kinase C which, because it phosphorylates proteins, activates them.

Adenylate cyclase activates ATP to a second messenger called cyclic adenosine monophosphate (cAMP). cAMP is rapidly inactivated by phosphodiesterases (See figures 1 & 2).

Enzyme-linked receptors

figure 3: mitogen activated protein kinases

Within enzyme linked pathways, an important factor is often the addition of an energised phosphate. The energised phosphate is donated to another molecule by an enzyme called a kinase. The energised phosphate is removed by phosphorylases. Amino acids with the ability to accept energised phosphates are tyrosine, serine and threonine.

Mitogen-activated protein kinases
Mitogen-activated protein (MAP) kinases belong to the serine-threonine family of enzyme-linked receptors. They are important in the growth and differentiation of many of the cells in the immune system. One of the most important activators of MAP kinases occurs through the activation of Ras.

Ras is attached to the cell membrane and, in its resting form, is bound to GDP. Activation of the Ras occurs when the GDP is phosphorylated. This increases the affinity of the Ras for a second molecule called Raf (MAP kinase kinase kinase). Raf then phosphorylates the first MAP kinase (MAP kinase kinase or MEK) on 2 sites. MEK then activates the final MAP kinase molecule (ERK). ERK can then phosphorylate a number of proteins which act integrally within the cell to affect transcription, translation and cell function (See figure 3).

figure 4: jak stat pathwayJanus-associated kinases
Janus-associated kinases (JAK) -STAT receptors are tyrosine enzyme linked receptors. These are among the most important receptors for cytokines. Cytokines bind to receptors which activate Janus kinases. These JAK molecules must be brought into close contact so they can cross-phosphorylate each other – four different JAK receptors are known (Jak 1, 2 and 3 and Tyk 2).

These activated JAKs can then, in turn, activate latent gene regulatory proteins called STATs (signal transducers and activators of transcription). Activated STATs form dimmers and are able to translocate to the nucleus where they can stimulate gene transcription.1 or more Jaks (1,2,3 or Tyk2) (See figure 4).

Nuclear Factor Kappa B
The NFκB pathway is one of the most important pro-inflammatory pathways in the immune system. Many of the other signaling pathways culminate in this final pathway. It is also essential in signaling of the innate immune receptors called Toll-like receptors and of Interleukin-1 (a cytokine). NFκB is found in the cytoplasm of cells bound to an inhibitory molecule called inhibitor of κB (IκB). The cascade is initiated when the receptor is activated. In turn, this activates a protein called My D88 which phosphorylates a serine-threonine enzyme known as IRAK (IL-1 receptor associated kinase). IRAK causes the dimerisation of inhibitor of κB kinase kinase which in turn phosphorylates IκB kinase. IκB kinase phosphorylates IκB causing it to dissociate from NFκB. The IκB is rapidly degraded in the cytoplasm and NFκB moves to the nucleus where it can stimulate the transcription of pro-inflammatory mediators.

Smad pathway
The smad pathway is a serine-threonine enzyme linked pathway. It is the primary receptor for the anti-inflammatory cytokine, transforming growth factor β (TGFβ). Similarly to the Jak-Stat pathway, two smad receptors must dimerise and cross-phosphorylate. This allows activation of the smad molecule by phosphorylation which can then dimerise with another smad molecule and move into the nucleus. In the nucleus, the smads can then promote or inhibit transcription.

Integrating cellular signaling

figure 5: cell receptor signalingThe T cell receptor is associated with a signaling chain which consists of 4 components – γ, δ, and 2ε chains – collectively called the CD3 molecule. The CD3 molecule is associated with various downstream molecules which enable the signal from the T cell receptor to be transmitted into the cell. Optimal T cell receptor signaling occurs when the tyrosine groups of the 2 small protein kinases, Lck and Fyn are phosphorylated and the inhibitory phosphates on the carboxy termini are removed. This allows binding of a molecule called Zap 70. Zap 70 can then activate a kinase called LAT which, in turn, activates phospholipase C which results in activation of DAG and IP3. Ras is also activated. Ras can activate the MAP kinase pathway. All pathways terminate in NFAT, NFκB and other transcription pathways (See figure 5).

The B cell receptor signals in a similar manner although in the B cell, the B cell receptor is cross-linked when it binds to antigen. This cross-linking results in activation of the adaptor protein BLNK and activation of Lck and Fyn.

Conclusion

Cell signaling is vital to the function of the immune system. Through the understanding signals function it becomes possible to manipulate the signals. In HIV infection, a G-protein coupled receptor (CCR5 or CXCR4) forms the major co-receptor for the virus. It has also been shown that the virus utilizes the cell signaling mechanisms for viral replication and viral immunobiological effects (for example – virions increase calcium production by activating the NFAT pathway – Chami, Oulès and Paterlini-Bréchot 2006). It is possible that these pathways may represent novel targets for rationale drug and vaccine design.

Peter H. Sugden et al.  (1997). Regulation of the ERK Subgroup of MAP Kinase Cascades Through G Protein-Coupled Receptors Cellular Signalling, Volume 9, Issue 5, August, Pages 337-351

Link to Abstract

Martin Oppermann. (2004). Chemokine receptor CCR5: insights into structure, function, and regulation Cellular Signalling, Volume 16, Issue 11, November , Pages 1201-1210

Link to Abstract

Charles Janeway et al. (2005). . Immunobiology 6th edition Churchill Livingston. Pages 203 -241

Link to Abstract

Bruce Alberts et al. (2002). Molecular Biology of the Cell 4th edition. Garland Science

Link to Abstract

Mounia Chami et al. (2006). Cytobiological consequences of calcium-signaling alterations induced by human viral proteins Biochimica et Biophysica Acta (BBA) – Molecular Cell Research, Volume 1763, Issue 11, November, Pages 1344-1362

Link to Abstract

Contributor

Dr Elizabeth Mayne
MBBCH

 
 
 
 
 
 
International Union of Immunological SocietiesUniversity of South AfricaInstitute of Infectious Disease and Molecular MedicineScience Education PrizesElizabeth Glazer Pediatric Aids FoundationAlere