The initial step of differentiation of the naive T-cells is the antigenic stimulation as a result of interaction of the genetically variable TCR and co-receptor CD4 with antigen-MHC II complex, presented by professional antigen presenting cells (APCs). Upon activation by T cell receptor (TCR)- and cytokine-mediated signaling, naive CD4+ T cells may differentiate into at least five major types of T helper (Th) cells, Th1, Th2, Th17, Tfh, and inducible T regulatory (iTreg) cells, that play a critical role in orchestrating adaptive immune responses to various microorganisms. A lack of sufficient stimulation from secondary signals like the cytokines, CD28, and Notch at this point may conversely lead to anergy or even apoptosis.IL-12 and IFNγ are two important cytokines for Th1 differentiation, with IFNγ playing the leading role in autocrine continuation and enforcement of cell fate. For Th2 differentiation, many cytokines including IL-4, IL-2, IL-7 and thymic stromal lymphopoietin (TSLP) may be involved, though eventually IL4 plays the leading role in autocrine self-reinforcement.
T-cell receptor activation causes two parallel events in cells destined for the Th2 fate. It directly stimulates a modest but significant increase in Gata3 mRNA, which rises steadily until ~24h after stimulation. In parallel, TCR engagement induces IL-2 production, which, in turn activates Stat5. The combination of early Stat5 activation and Gata3 induction leads to IL-4 production. This 'early IL-4' is TCR dependent but IL-4 independent. However, once the 'early IL-4' accumulates sufficiently, it signals through the IL-4R/Stat6 pathway to strikingly upregulate Gata3, which together with continued Stat5 activation, results in a further upregulation of IL-4 mRNA and thus to a positive feedback loop that results in the commitment to the Th2 phenotype.
The essential transcription factors of Th lineages are T-bet/Stat4 (Th1), Gata3/Stat5 (Th2), RORγt/Stat3 (Th17), and Foxp3/Stat5 (iTreg), respectively. T-bet is regarded as the master regulator for Th1 cell differentiation and IFNγ production.
Th1 helper cells are host immunity effectors against intracellular bacteria, viruses, and protozoa. They are triggered by IL-12, IL-2, tumor necrosis factor (TNF)-alpha, and their effector cytokine is IFN-γ. Th1 cells interact with CD8+ NK / CTL cells and macrophages to kill infected host cells. Th2 helper cells are host immunity effectors against extracellular parasites including helminths. They are triggered by IL-4 and their effector cytokines are IL-4, IL-5, IL-9, IL-10 and IL-13. They partner with B-cells, eosinophils, and mast cells to make humoral antibodies and granulocytic responses to large pathogens.