T-cell differentiation

The ability of naive T cells (cells that have not yet had antigen contact) to differentiate into Th1 and Th2 cells enables the immune system to react specifically to environmental stimuli that are converted by the antigen-presenting cells (APZ). Cytokines secreted by the APZs are essential for this. Antigen recognition in the presence of IL-12 causes the differentiation of Th1 cells, antigen recognition in the presence of IL-4 causes the differentiation of Th2 cells. This differentiation process is subject to strict control in order to avoid misregulation with consecutive diseases such as extrinsic bronchial asthma or extrinsic atopic eczema.

Transcription factors, also known as "nuclear messengers", play an important role in this control system. They are able to convert signals from the environment at the transcriptional level. They dock to promoter regions of genes to increase or decrease the expression of the respective genes. The transcription factor T-bet causes the Th1 differentiation, the transcription factor GATA-3 the Th2 differentiation. After some cell divisions under Th1 or Th2 inducing conditions, the corresponding differentiation pattern, Th1 or Th2, is firmly established. Transcription factors often interact with each other. Thus they influence each other in their efficiency. Genetic changes in transcription factors can lead to serious consequences in lymphocytic reactivity.

Differentiation of Th1 cells:

The differentiation process of Th1 cells begins after their stimulation with the release of interleukin-12 from antigen-presenting cells. The binding of IL-12 to its receptor on the surface of naive T cells results in phosphorylation and thus activation of STAT4 (= signal transducer and activator of transcription). STAT4 diffuses into the cell nucleus and initiates the transcription of IFNγ, the most important cytokine in Th1 cell differentiation. The increased expression of IFNγ leads to the activation of STAT1 via the phosphorylation of Janus tyrosine kinases (JAK) 1 and 2. STAT1 is in turn able to activate the transcription factor T-bet, the most important transcription factor in Th1 differentiation. T-bet also acts on the expression of IFNγ via a positive feedback mechanism. This type of feedback stabilizes and maintains the differentiation of Th1 cells. The expression of TBX21 (as well as another transcription factor = homeobox factor HLX1) suppresses the development of Th2 cells through the formation of Th2-specific cytokines.

The actual effectors of the Th1 immune response are macrophages, which ultimately eliminate the triggering agent (e.g. a pathogen) by phagocytosis. Activated macrophages secrete the pro-inflammatory cytokines IL-2, IL-5, lymphotoxin alpha and TNFalpha. They also secrete IL-12 and interferon gamma in order to stabilize the Th1 cell population via a stimulating feedback loop. if the homeostasis between the T cell populations shifts and an imbalance is established in favour of one T cell population, this leads to diseases of various kinds. An imbalance in favor of Th2 cells is associated with a suppressed Th1 response in various allergic diseases.

Differentiation of Th2 cells:

The Th2 differentiation process is dominated and controlled by the cytokines IL-4 and IL-13 . On naive T cells, binding to their receptors via Janus tyrosine kinases (JAK) 1 and 3 leads to activation of the transcription factor STAT6 (signal transducer and activator of transcription protein 6). STAT6 then interacts directly with GATA3 to initiate Th2 differentiation. GATA3 is essential for this. GATA3 is massively expressed in Th2 cells, but only slightly expressed in Th1 cells. Blocking GATA3 leads to the blockade of Th2 cytokine production in already differentiated Th2 cells and to the initiation of a Th1 reaction. Both transcription factors, TBX21 and GATA3, have the ability to inhibit the cytokine production of the other T subpopulation. In addition, GATA3 has the ability to stimulate its own expression independently of STAT6 in a kind of "auto-activation" and thus stabilize Th2 cell differentiation. Genetic variants of GATA3 have an influence on atopic phenotypes such as allergic rhinitis or atopic eczema. The effector mechanisms of the immunological Th2 response are mainly initiated by IL-4. IL-4 binds to naive B cells and thereby induces the formation of allergen-specific IgE. Characteristic type I allergic reactions, e.g. the production of allergen-specific IgE from B cells, are mediated primarily by the two Th2-specific cytokines IL-4 and IL-13.