Cytokines
Cytokines are the soluble molecules emitted by the different actors of immunity in order to ensure temporal-spatial coordination. Indeed, all the elements contributing to the immune response are very heterogeneous, both in space (the different actors are in different places in the body at a given time), and in time (the different actors are at different stages of maturation at a given time).
Given the finesse and adaptability of the immune response, the range of information exchanged must necessarily be very broad. Thus, cytokine diversity is very important to meet this need.
The different names of cytokines
Cytokines refer to all molecules allowing communication between immune cells. However, we can find other names for these molecules.
- Interleukins (abbreviated IL): “between leukocytes”. However, it tends to be abandoned because this classification is outdated (example of TNF which has all the properties of an interleukin but not the name).
- Chemokines: subcategory of cytokines having in particular a chemoattractant power, that is to say inducing cell mobility.
Molecular description
Cytokines are small proteins with a molecular mass around 30kDa. Most are glycosylated which contributes to stability but is not necessary for cytokine activity.
Common properties of cytokines
- Pleiotropy: a cytokine may induce different effects.
- Redundancy: two different cytokines may have the same effect.
- Synergy: the combined effect of two cytokines is not necessarily the addition of the effect of each cytokine, but can induce a tenfold or different effect.
- Antagonism: the effects of one cytokine can inhibit those of another cytokine.
- Induction of cascades: the action of a cytokine on a target cell can induce the secretion of other cytokines with different effects.
Diversity of cytokines
Diversity of functions
Cytokines regulate the intensity and duration of the immune response because they are responsible for the mechanisms of activation, proliferation, and differentiation of target cells. They have countless functions, including:
- the change in expression of membrane molecules (adhesion molecules, activation co-signals, HLA molecules).
- the change in expression of membrane receptors (receptors for different cytokines, whose conformation changes modify their affinity for cytokines).
- the change of transcriptional program.
- the change in organisation of the cytoskeleton and organelles.
- the change in cytokine secretion...
Diversity of secretion modes
Cytokines may be secreted in an autocrine, paracrine, or endocrine mode.
- Autocrine: secretion of the cytokine for the specific benefit of the transmitting cell
- Paracrine: secretion of the cytokine for the benefit of a spatially close immune actor
- Endocrine: secretion of the cytokine for the benefit of an actor (of immunity or not) spatially distant
These secretion modes are not exclusive (e.g., IL-2 acts via these three secretion modes).
Immunity diversity
There are innate immunity cytokines, such as adaptive immunity cytokines, and cytokines involved in both innate and adaptive immunity (e.g., type 1 interferon).
Location diversity
The overwhelming majority of cytokines are soluble, although some cytokines can be membrane bound.
Six families of cytokines are described:
- Interleukin-1 family: primarily involved in pro-inflammatory innate immunity, including increased capillary permeability, lymphocyte recruitment, and systemic effects of inflammation.
- Haematopoietin family: historically includes the cytokines effectively involved in hematopoiesis, whose tertiary configuration is based on a bundle of four antiparallel helices. By extension, other cytokines with the same structure have been categorised in this family, although their functions are not essentially haematopoietic, but as diverse as the proliferation of lymphocytes, differentiation of B cells into plasma cells, etc.
- Interferon family: There are three major types of interferons, all of which increase the expression of Class I and II HLA molecules on the surface of cells.
- Type I interferons: interferon α and interferon β, secreted after recognition of viral patterns by the PRRs. Interferon α is secreted by activated macrophages and dendritic cells, while interferon β is secreted by fibroblasts.
- Type II interferons: γ interferon produced by NK cells and T cells, directs the immune response towards a cytotoxic response (increase in Th1 cells, activation of macrophages, differentiation of CD8+ T cells)
- Type III interferons: interferon λ, interferon delta, interleukin 10 (IL-10)
- Family of tumour necrosis factors: these are particular cytokines, because they are most often anchored in the cell membrane.
- Interleukin 17 family: recently discovered, this family brings together mainly pro-inflammatory cytokines at the interface of innate and adaptive immunity.
- Chemokine family: they include cytokines specialised in attracting different elements of the immune response. This attraction occurs according to a concentration gradient of chemokines, which attract cells possessing the dedicated receptor towards the source of synthesis. These chemokines can attach in particular to the walls of the vessels, and therefore guide the elements of immunity in the vessels.
Cytokine receptors
Each cytokine can bind to more than one receptor and a receptor can bind multiple cytokines. In total, around twenty receptors recognise around thirty cytokines. Most of the time, these receptors are transmembrane
The sensitivity of a cell to a cytokine stimulus is regulated by:
- signal intensity
- the receptors sensing this signal (quantity of expression and affinity for the cytokine)
In general, there is a very strong affinity of the receptor for the cytokine which is secreted near the receptor (concept of immunological synapse).
Immunological synapses explain why systemic cytokine concentrations must becarefully interpreted , and the topography of cellularinteractions must be taken into account.
How can we explain that the same cytokine can have distinct effects on different cell types?
1. Cellular expression of cytokine receptors
The expression of cytokine receptors varies depending on the cell types, but also on their state of activation.
For example, a T cell after activation – that is to say after its encounter with the antigen – will overexpress the IL-2 receptor (proliferation signal) as well as the IL-4 receptor (differentiation signal). Thus the T cells which have encountered the antigen will continue their maturation/proliferation process, while the naive T cells (those which have not encountered the antigen) will remain inert until this encounter.
2. Co-signals
Signal integration and cellular response do not only depend on a cytokine but also:
- on other cytokines in the environment
- on receptors expressed at time T by the cell
- on the state of the cell and its environment
What needs to be remembered
Cytokines are small molecules, most often soluble, acting as messengers of the immune system. They have very different modes of action and are capable of very finely regulating the immune response. It should be noted that the pleiotropy and antagonism properties of cytokines make it difficult to assign a property to a cytokine; a cell actually receives dozens of concomitant cytokine signals thanks to its arsenal of receptors, depending on the cell type and the activation state. The integration of all these signals makes the cellular response unique.
