Fig. 2.

A model of T_AIM differentiation regulators. During conventional CD8⁺ T cell differentiation CD8 single positive (CD8 SP) thymocytes exit the thymus and enter the periphery as naïve (T_N) CD8⁺ cells. Upon encountering a foreign antigen presented on the MHC class I complex of an antigen-presenting cells, T_N cells become activated and differentiate into short-lived effector and long-lived true memory (T_TM) cells. T_TM cells provide a rapid immune response when re-activated, thereby ensuring an effective secondary immune response. In addition to the conventional T_TM cells, memory-phenotype cells also arise in an antigen-independent manner. The differentiation of the antigen-inexperienced memory T cells (T_AIM) is guided by two main signals: cytokines and T cell receptor (TCR) signaling. Increased IL-4 levels in the thymus, either as a result of infection, or strain specific, or caused by deletion of the epigenetic modulator EZH2 or JARID2, induces T_AIM differentiation in CD8 SP thymocytes. These cells have increased expression of cytokine genes and memory genes, including the key transcription factor EOMES. EOMES expression can also be upregulated directly by IL-4. A specific level of heightened TCR signaling also affects EOMES expression and results in the upregulation of CD5 on naïve CD8 single positive thymocytes that are more prone to become T_AIM cells. Upon migration to the periphery, these CD5^high cells already express mildly increased levels of cytokine genes and memory genes. IL-15 signaling further drives these cells to become T_AIM cells. The histone modifiers DOT1L and HDAC7 prevent T_AIM differentiation by regulating transcriptional and epigenetic networks that keep cells in a naïve state. Furthermore, DOT1L and, possibly also, HDAC7 are involved in regulating TCR signaling