Memory CD8+ T cell differentiation

Abstract

In response to infection or effective vaccination, naive antigen-specific CD8+ T cells undergo a dramatic highly orchestrated activation process. Initial encounter with an appropriately activated antigen-presenting cell leads to blastogenesis and an exponential increase in antigen-specific CD8+ T cell numbers. Simultaneously, a dynamic differentiation process occurs, resulting in formation of both primary effector and long-lived memory cells. Current findings have emphasized the heterogeneity of effector and memory cell populations with the description of multiple cellular subsets based on phenotype, function, and anatomic location. Yet, only recently have we begun to dissect the underlying factors mediating the temporal control of the development of distinct effector and memory CD8+ T cell sublineages. In this review we will focus on the requirements for mounting an effective CD8+ T cell response and highlight the elements regulating the differentiation of effector and memory subsets.

Figure 1

Early cell fate determination model of effector and memory CD8⁺ T-cell differentiation. In this model naive CD8⁺ T cells become activated and form an early effector CD8⁺ T-cell population, which is CD127^low KLRG1^low. Next, three populations of effector cells can be identified by the peak of the CD8⁺ T-cell response: short-lived effector cells (SLEC) that are CD127^low KLRG1^high CD62L^low, effector memory cells (T_EM) memory precursor effector cells (MPEC) that are CD127^high KLRG1^low CD62L^low, and central memory cells (T_CM) MPEC that are CD127^high KLRG1^low CD62L^high. Over time the SLEC population is lost through apoptosis, while the MPEC population remains long term in the host forming the memory CD8⁺ T-cell population. Additionally, with time the memory population transitions from being predominately T_EM in phenotype to T_CM in nature, and this is the result of the increased homeostatic proliferation rate of the T_CM population. KLRG1, killer cell lectin-like receptor G1; Ag, antigen; CpG, unmethylated CpG containing oligonucleotide.

Figure 2

Model of CD62L regulation by T-cell receptor (TCR) stimulation and γ_c-cytokines. Antigen-specific CD8⁺ T cells are activated following engagement of the TCR with cognate peptide antigen presented in the context of major histocompatibility complex (MHC)-I. This leads to the activation of numerous signaling molecules, including the p110δ subunit of phosphatidylinositol-3-kinase (PI[3]K). This leads to activation of Erk1/2, which will then phosphorylate the TACE/Adam17 protease. Following phosphorylation the TACE/Adam17 protease will translocate to the cell membrane where it can cleave CD62L from the cell surface. This results in the transient early downregulation of CD62L. More sustained modulation of CD62L expression occurs at the genetic level and appears to be regulated, at least in part, by the γ_c-cytokines IL-2 and IL-15. IL-2 strongly activates the p110δ subunit of PI(3)K that will subsequently activate the mammalian target of rapamycin (mTOR) complex, while IL-15 only weakly activates this pathway. mTOR then regulates Klf2 activity, which is known to enhance the expression of CD62L, CCR7, and S1P₁.