Cytokines play an important role in the activation of innate immunity and determining the class of response of cells of adaptive immunity. Their physiological roles are still being intensively investigated. Here are some of the most important cytokines that can regulate development of innate immunity cells and adaptive immunocytes after activation in the periphery:
|IFN-γ||Activated CD4 and CD8 T (Th1, Tc1); activated NK and NKT|
|IFN-α/β||Mature plasmocytoid DC; mature DC type 2|
|IL-2||Activated CD4 T; Th1; CD4 T memory cells|
|IL-4||Innate cells type 2; mast cells; activated Th2, NKT|
|IL-6||Monocytes; activated macrophages; activated Th2; fibroblasts|
|IL-10||Immature DCs; quiescent Mø, activated Th2; Th3; Th9; Tregs|
|IL-12||DC type 1; activated macrophages; activated B cells|
|IL-13||Activated Th2, innate type 2 cells|
|IL-22||Activated Th22 (and Th17)|
|IL-23||DC type 1; macrophages|
|IL-35||Regulatory T cells (IL-35 producing)|
|TNF||Activated macrophages (TNF-α), activated Th1 (TNF-β)|
|TGF-β||Quiescent macrophages; Tregs (CD4, CD25, Foxp3), Th3,Th9|
The cytokines influencing Th1 development are IL-2, IL-12 (p70), IL-18, and IL-27. The Th0 cells can develop into Th1-type effector cells under the influence of the master transcription factor T-bet, which is promoted by microbial agents and viruses. The cytokines involved include IFN-γ, but at the very beginning it seems that IL-27 (in the early response) and IL-12(p70) has the major influence, but IL-18 and also RANK ligand can promote their development. IL-12 increases the expression of receptor for IFN-γ, which in turn can act on the polarization of this subpopulation. Their differentiation is halted by IL-4, IL-10, and IL-21. IL-23 promotes the proliferation of Th1 CD4 memory cell population.
The master regulator transcription factor is GATA3, which can be upregulated via IL-4 action and STAT-6. IL-4 is sufficient, but is not the only necessary factor for Th2 development. Th2 can develop under the influence of cytokines such as TSLP, IL-25, and IL-33 (and IL-15 in humans, as well as IL-31). Indirectly, IL-13 is also involved. The cells of innate helper type 2 (Ih2) also called nuocytes, MPP, and NHC cells upon stimulus from IL-25 and IL-33 produce IL-13 that in turn promote mast cells, macrophages (type 2), and basophils to secrete IL-4, effectively steering the response towards the Th2 type.
IL-4 is involved in the positive feedback loop that can generate more of the Th2 subset cells from the Th0 stage. This pathway can be inhibited by the action of IFN-γ or TGF-β. IL-13 can possibly act via a wider loop by generating more Th2 cells via mast cells, basophils, and type-2 macrophages.
The cytokines influencing Th17 development are TGF-β and IL-6 from the naïve T cells, and from the activated CD4 T cell stage IL-1, IL-21, and IL-23 are involved. There are some concerns as to whether this is a stable population, because two recipes in vitro for their generation can yield the same result. TGF-β plus IL-6 and IL-1 can generate Th17 cells, but also TGF-β plus IL-21 followed by IL-23 can do the same. Furthermore, some sources also mention TNF for the formation of an unusual sub-subset of Th17. Human Th17 cells are very hard to establish in vitro, unlike mouse Th17 subsets, which are easily polarized. The generation of Th17 can be inhibited by IFN-γ, IL-2, IL-4, IL-12(p70), and IL-27.
NKT cells can be generated under the influence of the IL-15 (from thymic emigrants). Upon activation by cells that modulate their MHC antigens, or by directly recognizing some pMHC combinations, they secrete IL-4, IL-17A, and IFN-γ, influencing the generation of other subsets in the initial phase as well as in the regulation of the immune response.
IFN-γ: causes switch to IgG1 and IgG3 isotypes (in the mouse—IgG2a).
IL-4: causes development of plasma cells that secrete IgE and IgG4.
TGF-β: causes development of plasma cells that secrete IgA antibodies;
IL-2: enhances growth and multiplication of B lymphocytes.
IL-6: stimulates development of activated B cells into plasma cells.
IL-7: promotes development of precursors of B cells during development in the bone marrow.
Dembic Z. The Cytokines of the Immune System: The Role of Cytokines in Disease Related to Immune Response[M]. Academic Press, 2015.