Figure 2.
Stages of T-cell development and differentiation. (A) T-cell lymphopoiesis initiates with precursor HSC in the bone marrow (BM), the primary lymphoid organ; and CLPs in BM are directed to T-cell lineage fate via IL7/NOTCH signaling. CLP enters the cortex region of the thymus and undergoes a series of differentiation stages including β-selection and TCR repertoire phase, which can be identified through cell surface receptors (CD44 and CD25). T cells undergo a dual selection process, positive selection for compatibility of their TCR with self-MHC molecules and negative selection against autoantigenic peptides before leaving the thymus to form the peripheral T-cell repertoire. Double-positive cells differentiate toward CD4+ T cells through ThPOK and GATA3 expression, as well as a strong TCR signal, as well as toward CD8+ T cells through RUNX3 and NOTCH expression and a weak TCR signal. Although the vast majority of cells express an αβ TCR, a small subset expresses an alternative TCR composed of γ and δ chains (γδ T cells) and diverge early place at the DN3A stage in T-cell development and mostly become residents of mucosal sites. (B) In the peripheral secondary organs, the CD4+ T cells can differentiate into distinct TH subsets (TH1, TH2, TH9, TH17, Treg, and TFH), dependent upon stimulation from APC, their coreceptors, and cytokine milieu. Several PTCL subtypes show a similar cell state or transcriptomics associated with these TH subsets precursors. TH1 cells are characterized by the expression of key master regulators or TFs (ie, STAT4 and TBX21). These cells require interleukin-12 (IL-12) signaling for their differentiation and secrete IFN-γ, IL-2, and lymphotoxin. TH2 cells express TFs, STAT6 and GATA3, require IL-4, and produce IL-4, IL-5, and IL-13, important for TH2 differentiation. TH9 cells secrete IL-9, require TGF-β and IL-4, and are characterized by the expression of PU.1 and IRF4. TH17 expresses STAT3 and RORγt as key TFs, produces IL-17 and TNF-α, and requires IL-1β, TGF-β, IL-6, and IL-23. Tregs differentiate with TGF-β and IL-2, express FOXP3 and STAT5, and release TGF-β and IL-10 to suppress immune response. TFH cells produce IL21, with key TFs being BCL6 and STAT3, and require IL-6 signaling and ICOS-L. CD8+ T cells serve a cytotoxic function, regulated by PRMD1 and TBX21, and release IL-2, IFN-γ, and TNF-α. These cells can be further differentiated into CD8+ TEM and TCM via EOMES and BCL6, respectively. APC, antigen-presenting cell; CLP, common lymphoid progenitor cell; IFN-γ, interferon gamma; TCM, central memory T cell; TEM, effector memory T cell; TGF-β, transforming growth factor β; TNF-α; tumor necrosis factor α.

Stages of T-cell development and differentiation. (A) T-cell lymphopoiesis initiates with precursor HSC in the bone marrow (BM), the primary lymphoid organ; and CLPs in BM are directed to T-cell lineage fate via IL7/NOTCH signaling. CLP enters the cortex region of the thymus and undergoes a series of differentiation stages including β-selection and TCR repertoire phase, which can be identified through cell surface receptors (CD44 and CD25). T cells undergo a dual selection process, positive selection for compatibility of their TCR with self-MHC molecules and negative selection against autoantigenic peptides before leaving the thymus to form the peripheral T-cell repertoire. Double-positive cells differentiate toward CD4+ T cells through ThPOK and GATA3 expression, as well as a strong TCR signal, as well as toward CD8+ T cells through RUNX3 and NOTCH expression and a weak TCR signal. Although the vast majority of cells express an αβ TCR, a small subset expresses an alternative TCR composed of γ and δ chains (γδ T cells) and diverge early place at the DN3A stage in T-cell development and mostly become residents of mucosal sites. (B) In the peripheral secondary organs, the CD4+ T cells can differentiate into distinct TH subsets (TH1, TH2, TH9, TH17, Treg, and TFH), dependent upon stimulation from APC, their coreceptors, and cytokine milieu. Several PTCL subtypes show a similar cell state or transcriptomics associated with these TH subsets precursors. TH1 cells are characterized by the expression of key master regulators or TFs (ie, STAT4 and TBX21). These cells require interleukin-12 (IL-12) signaling for their differentiation and secrete IFN-γ, IL-2, and lymphotoxin. TH2 cells express TFs, STAT6 and GATA3, require IL-4, and produce IL-4, IL-5, and IL-13, important for TH2 differentiation. TH9 cells secrete IL-9, require TGF-β and IL-4, and are characterized by the expression of PU.1 and IRF4. TH17 expresses STAT3 and RORγt as key TFs, produces IL-17 and TNF-α, and requires IL-1β, TGF-β, IL-6, and IL-23. Tregs differentiate with TGF-β and IL-2, express FOXP3 and STAT5, and release TGF-β and IL-10 to suppress immune response. TFH cells produce IL21, with key TFs being BCL6 and STAT3, and require IL-6 signaling and ICOS-L. CD8+ T cells serve a cytotoxic function, regulated by PRMD1 and TBX21, and release IL-2, IFN-γ, and TNF-α. These cells can be further differentiated into CD8+ TEM and TCM via EOMES and BCL6, respectively. APC, antigen-presenting cell; CLP, common lymphoid progenitor cell; IFN-γ, interferon gamma; TCM, central memory T cell; TEM, effector memory T cell; TGF-β, transforming growth factor β; TNF-α; tumor necrosis factor α.

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