Thymic seeding progenitors (TSPs), originating from the bone marrow, enter the thymus and pass through six double negative (CD4-/CD8-) stages: DN1, DN2a, DN2b, DN3a, DN3b, and DN4 (reviewed in Sun et al. 2023). T cell receptor components are initially expressed in DN3b cells. Double negative 4 (DN4) cells then express both CD4 and CD8 and are designated double positive (DP) cells. DP cells then differentiate into single positive cells: naive (not yet activated by antigen) CD4+ T cells and naive CD8+ T cells.
Upon stimulation of the T cell receptor (TCR) by antigen, CD4+ T cells are directed by other external factors, notably cytokines, to differentiate into various types of T helper cells. The different types of T helper cells are characterized by master regulatory transcription factors and secreted effector cytokines (reviewed in Lee 2023, Sun et al. 2023):
T helper 1 (Th1) cells are regulated by TBX21 (T-bet) and secrete interferon gamma (IFNG).
T helper 2 (Th2) cells are regulated by GATA3 and secrete IL4, IL5, and IL13.
T helper 9 (Th9) cells are regulated by IRF4 and SPI1 (PU.1) and secrete IL9, IL10, and IL21.
T helper 17 (Th17) cells are regulated by RORC isoform t (RORgammat) and STAT3 (reviewed in Imam et al. 2018) and secrete IL17A, IL17F, and IL22.
T helper 22 (Th22) cells are regulated by TBX21 and STAT3 and secrete IL22, but not IFNG or IL17 (reviewed in Imam et al. 2018).
T follicular helper (Tfh) cells are regulated by BCL6 and secrete IL21.
T regulatory (Treg) cells are regulated by FOXP3 and secrete IL10.