Generation of effector CD8+ T cells and their conversion to memory T cells

Abstract

Immunological memory is a cardinal feature of adaptive immunity. We are now beginning to elucidate the mechanisms that govern the formation of memory T cells and their ability to acquire longevity, survive the effector-to-memory transition, and mature into multipotent, functional memory T cells that self-renew. Here, we discuss the recent findings in this area and highlight extrinsic and intrinsic factors that regulate the cellular fate of activated CD8+ T cells.

Fig. 1. Generation of effector CD8⁺ T cells and progressive differentiation into memory T cells

In response to infections, naive CD8⁺ T cells become activated, proliferate rapidly, and differentiate into a heterogeneous pool of effector CD8⁺ T cells. Most cells terminally differentiate into end-stage effectors that have a shortened lifespan and die following infection, whereas a smaller subset of cells differentiates into memory cell precursors that can further mature into functional memory cells that self-renew. Exposure to high levels of proinflammatory cytokines, such as IL-12, IFN-γ, and IL-2, causes upregulation of T-bet and Bilmp-1 as well as increased mTOR activity in activated CD8⁺ T cells, which in turn promotes effector cells to terminally differentiate and die via Bim-dependent apoptosis. By contrast, a group of cells upregulate BCL-6, Bmi-1, Tcf7, and possibly Eomes when they either circumvent high levels of proinflammatory cytokines or possibly encounter pro-memory signals. They can also switch from mTOR-mediated anabolic state to AMPK/FAO-mediated catabolic state following growth factor withdrawal and survive effector-to-memory transition by upregulating anti-apoptosis factors, such as Bcl-2 and Mcl-1. Between these two cell subsets (SLEC in dark purple and MPEC in orange), additional types of effector CD8⁺ T cells exist that appear to display a mix of terminally differentiated and memory precursor cell properties and have intermediate lifespans and proliferative potential. After pathogen clearance, effector CD8⁺ T cells give rise to diverse subsets of memory T cells, including end-stage T_EM, T_TM, T_EM, and T_CM. End-stage T_EM cells are more effector like, have poor recall ability, and gradually decay from the memory pool. T_TM continually differentiate into T_CM that persist for a long term via homeostatic turn over, acquire homing ability to SLOs, produce IL-2, and mount robust secondary response upon recall. T_EM cells usually reside in periphery tissues and retain their cytolytic activity, thereby providing immediate effector function at the portal of pathogen entry, but exhibiting reduced proliferative capacity. IL, interleukin; IFN-γ, interferon-γ; mTOR, mammalian target of rapamycin; AMPK, 5′-adenosine monophosphate-activated protein kinase; FAO, fatty acid oxidation; SLEC, short-lived effector cell; MPEC, memory precursor effector cell; T_EM, effector memory T cells; T_TM, transitional T_EM; T_CM, ‘central’ memory CD8⁺ T cells; SLO, secondary lymphoid organ.