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. 2020 Jul 23;34(10):2592–2606. doi: 10.1038/s41375-020-0990-y

Fig. 3. Schematic model of AITL generation.

Fig. 3

In the bone marrow (BM), somatic mutations in TET2 (or TET2 plus DNMT3A; marked as TET2 and DNMT3A) result in clonal hematopoiesis. TET2 alone or TET2 plus DNMT3A mutated hematopoietic stem cells (HSC) can give rise to thymocytes. TET2 plus DNMT3A mutated HSC generate more CD4+ T cells than CD8+ T cells. TET2* indicates TET2 mutation alone or TET2 plus DNMT3A mutations. TET2 alone or TET2 plus DNMT3A mutated naive CD4+ T cells are primed to Tfh cells by the contact with myeloid DC cells, and migrate to the T-B border. The TET2 mutation (or TET2 plus DNMT3A mutations)-carrying Tfh-primed cells contact with the TET2-mutated activated B cells, then acquire the RHOAG17V mutation (RHOA) before or after differentiation into Tfh cells (Tfh). These Tfh cells should further interact with B cells (“B”) derived from activated B cells at the follicle-destroyed lymph nodes. The Tfh cells carrying TET2 (or TET2 plus DNMT3A) plus RHOA mutations may further acquire the IDH2 mutation (IDH2). RHOA mutation alone or RHOA plus IDH2 mutations are designated as RHOA*. Ultimately, mutations in TCR-related genes (TCRr) are acquired. TET2-mutated B cells are infected with EBV and/or acquire mutations in genes such as NOTCH1. These Tfh cells and B cells with individually accumulated mutations still contact and activate each other through ICOS-L and ICOS ligation and still unknown mechanisms (designated as “?”). Some of the B cells take a morphology as immunoblasts or HRS cells, and B-cell lymphoma arises. See the text for the further scenario. LN lymph nodes, Thy thymus. HSC hematopoietic stem cell, naive CD4+ naive CD4+ T cell, Tfh-primed Tfh-primed CD4+ T cell, Tfh follicular helper T cell, activated B activated B cell, Th17 T helper 17 cell, Th1 T helper 1 cell, Th2 T helper 2 cell, eosino eosinophil, plasma plasma cell, FDC follicular dendritic cell, HEV high endothelial venule. ICOSL ICOS ligand, MHC/Ag antigen presented on major histocompatibility complex, TCR T-cell receptor, BCR B-cell receptor, VEGF vascular endothelial growth factor.