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.The essential transcription factors of Th lineages are T-bet/Stat4 (Th1), Gata3/Stat5 (Th2), RORγt/Stat3 (Th17), and Foxp3/Stat5 (iTreg). T-bet is regarded as the master regulator for Th1 cell differentiation and IFNγ production. The cell activation process takes place over days, involving initial contact, primary stimulation, secondary stimulation, synapse formation, activation, a complex program of changes in transcription, signalling, and other systems, and proliferation. Later, T-cells can turn into memory cells, or die (anergy, apoptosis) due to insufficient stimulation.
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. 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.