Decisions on the Road to Memory

Abstract

A fundamental property of the adaptive immune system is the ability to generate antigen-specific memory, which protects against repeated infections with the same pathogens and determines the success of vaccination. Immune memory is built up alongside a response providing direct protection during the course of a primary immune response. For CD8 T cells, this involves the generation of two distinct types of effector cells. Short lived effector cells (SLECs) confer immediate protection, but contribute little to the memory repertoire. Memory precursor effector cells (MPECs) have the ability to respond to survival signals and develop into memory cells. These two types of cells can be distinguished on the basis of surface markers and express distinct genetic programs. A single naive CD8 T cell can give rise to both MPEC and SLEC daughter cells. This may involve an initial asymmetric division or depend on later instructive signals acting on equipotent daughter cells. Strong inflammatory signals favor the generation of SLECs and weaker inflammation favors the generation of MPECs. A distinguishing feature of MPECs is their ability to persist when most effector cells die. This survival depends on signals from the IL-7 receptor, which induce expression of anti-apoptotic factors. MPECs are therefore characterized by expression of the IL-7 receptor as well as the CCR7 chemokine receptor, which allows homing to areas in lymphoid organs where IL-7 is produced. Critical for persistence of MPECs is further their responsiveness to myeloid cell derived IL-15, which instructs these cells to switch their metabolic programs from glycolysis associated with rapid proliferation to fatty acid oxidation required during a more resting state. As the mechanisms determining generation of immunological memory are unraveled, opportunities will emerge for the improvement of vaccination strategies.

Sensitivity to Restimulation-Induced Cell Death Is Linked to Glycolytic Metabolism in Human T Cells

“…It will be important to determine whether certain effector T cells that modulate glycolysis and switch to OXPHOS, fatty acid oxidation (FAO), and/or autophagy can preferentially enter the memory pool in part by escaping RICD (5, 31, 36). Recently identified effector T cell subsets such as short-lived effectors (SLEC) and memory precursor (MPEC) T cells differ in their survival and potential for memory formation (37, 38), which may be influenced by a divergence in glycolysis-dependent RICD sensitivity. For example, exposure to cytokines like IL-15 might protect selected effectors from RICD by facilitating a switch from aerobic glycolysis to OXPHOS (4, 38-40).…”

“…Recently identified effector T cell subsets such as short-lived effectors (SLEC) and memory precursor (MPEC) T cells differ in their survival and potential for memory formation (37, 38), which may be influenced by a divergence in glycolysis-dependent RICD sensitivity. For example, exposure to cytokines like IL-15 might protect selected effectors from RICD by facilitating a switch from aerobic glycolysis to OXPHOS (4, 38-40). …”

Low hemagglutinin antigen dose influenza vaccines adjuvanted with AS03 alter the long-term immune responses in BALB/c mice

“…However, there were also important differences in the responses generated by these different formulations. Although adjuvant-induced inflammation can sometimes promote short-rather than longterm immunity, 34,35 we found that the LD-AS03-adjuvanted formulations were the most effective at inducing long-term memory responses in our mouse model. These formulations elicited very different antigen-specific cytokine/chemokine profiles and patterns of antigen-specific CD4C T cells in re-stimulated splenocytes compared to the HD-unadjuvanted vaccine.…”

Chemokines: Critical Regulators of Memory T Cell Development, Maintenance, and Function

“…In the Asymmetrical Division hypothesis, the SLEC vs MPEC fate decision is made during the first cell division via asymmetrical partitioning of factors, such as atypical protein kinase C, mTOR, and c-myc (Arsenio, Metz, & Chang, 2015; Pollizzi et al, 2016; Verbist et al, 2016). Studies have shown that the daughter T cell proximal to the antigen-presenting cell has a greater propensity to differentiate into a SLEC, whereas the distal daughter T cell preferentially differentiates into a MPEC (Amsen, Backer, & Helbig, 2013; Gerritsen & Pandit, 2016). While this early partitioning of cellular factors likely plays a role, studies suggest that subsequent signals can influence T cell fate.…”