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. 2022 Dec 7;13:1059042. doi: 10.3389/fimmu.2022.1059042

Figure 2.

Figure 2

The development, migration, maintenance, and proliferation of TCRαβ+ CD8αα+ and TCRγδ+ CD8αα+ IELs. Both types arise from thymic IELps. TP cells become DN cells by regulation from E8I, E8II, IL-15, Bcl-2, and RasGRP1. E8I and E8II can suppress the expression of CD8αβ. RasGRP1 contributes to the transmission of weak TCR signals in the process of selection. Besides, c-Myc controls the development of TCRαβ+ CD8αα+ IELps via IL-15 and Bcl-2. After agonist selection, pre-mature TCRαβ+ CD8αα+ IELps further develop with the help of T-bet, TGF-β, and PD-1. Mature TCRαβ+ CD8αα+ IELps migrate to the intestine directly with the help of S1PR1, α4β7, CD103, and CCR9. Besides these molecules, TCRγδ+ CD8αα+ IELps also require GPCR18 and GPCR55 for localization and regulation of their accumulation. After IELps arrive in the intestine, the expression of CD5 and CD90 is downregulated, while the expression of T-bet is upregulated, exhibiting the phenotype of CD8αα. Meanwhile, the crosstalk between commensal bacteria, IECs, and CD8αα IELs contributes to the maintenance and proliferation of CD8αα cells, via NOD2 signaling, TLRs signaling, RIG-I signaling, IL-15, and other signaling pathways. In addition, BTNL1, BTLN3, BTNL6 and BTNL8 could promote the maturation and expansion of γδ IELs.