Signals for antigen-independent differentiation of memory CD8+ T cells

Abstract

Conventional CD8⁺ memory T cells develop upon stimulation with foreign antigen and provide increased protection upon re-challenge. Over the past two decades, new subsets of CD8⁺ T cells have been identified that acquire memory features independently of antigen exposure. These antigen-inexperienced memory T cells (T_AIM) are described under several names including innate memory, virtual memory, and memory phenotype. T_AIM cells exhibit characteristics of conventional or true memory cells, including antigen-specific responses. In addition, they show responsiveness to innate stimuli and have been suggested to provide additional levels of protection toward infections and cancer. Here, we discuss the current understanding of T_AIM cells, focusing on extrinsic and intrinsic molecular conditions that favor their development, their molecular definitions and immunological properties, as well as their transcriptional and epigenetic regulation.

Keywords: Antigen-inexperienced memory; CD8+ T cell; Innate memory; Virtual memory.

Fig. 1

Antigen-inexperienced memory T cell (T_AIM) differentiation: A delicate balance of integrated signaling. The quality of TCR/co-receptor and cytokine signals are central to T_AIM differentiation. Cytokines most important for T_AIM cells are IL-4 in the thymus and IL-15 in the periphery. Ablation of these cytokines or their receptors leads to a strong reduction in the number of T_AIM cells. The balance between cytokine and TCR signals determines whether a CD8⁺ T cell remains naïve (T_N) or differentiates into a T_AIM cell. The TCR and cytokine signals lead to altered transcriptional output, which is further modulated by epigenetic mechanisms. The extracellular signals, and fluctuations in expression of genes involved in these signaling pathways due to transcription dynamics, as well as differentiation and proliferation together affect T_AIM differentiation. The net result is a dynamic population of T_AIM cells in mouse and humans

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