Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells

Abstract

Weak T cell antigen receptor (TCR) signals from contact with self ligands act in synergy with antiapoptotic signals induced by interleukin 7 (IL-7) to promote the survival of naive T cells in a resting state. The amount of background TCR signaling in naive T cells is set by post-thymic TCR tuning and operates at an intensity just below that required to induce entry into the cell cycle. Costimulation from higher concentrations of IL-7 and other common γ-chain cytokines can induce T cells to undergo homeostatic proliferation and conversion into cells with a memory phenotype; many of these memory phenotype cells may be the progeny of cells responding to self antigens. The molecular mechanisms that control the conversion of naive resting T cells into memory-phenotype cells TCR-dependent in normal animals are beginning to be understood.

Figure 1

TCR tuning and signaling pathways involved in maintaining naïve T cell survival in a quiescent state. A) TCR tuning at the proximal stage requires upregulation of negative regulator adapter protein Cbl-b and CD5-associated SHP-1 to block Vav activation. Further downstream, repression of NFκB activity is involved through Foxj1- and Foxo3a-induced synthesis of the NFκB inhibitor, IkB. Inhibition of calcineurin-mediated NFAT translocation to the nucleus is prevented in resting T cells by the autoinhibitory domain of calcineurin. Cell cycle arrest is mediated by a variety of transcription factors, such as Tob and KLF4, which downregulate expression of genes essential for cell cycle progression. B) Several signaling pathways are essential for survival of naïve T cells. Impaired lifespan of naïve T cells is seen in mice lacking Vav1, WASP, the adaptor Nck, the RNA-binding protein, hnRNPLL, a Rho-Rac GTP exchange factor, Dock 8, and the β3 regulatory subunit of voltage-gated calcium channels. Lipid rafts have been shown to enhance TCR signaling and responsiveness to homeostatic cytokines.

Figure 2

Positive selection to self-MHC ligands on thymic epithelial cells (TEC) has at least two purposes. First, selection of a T cell repertoire that can react weakly to self-pMHC ligands in the periphery ensures that naïve T cells receive continuous tonic TCR signals; these signals together with recognition of IL-7 on fibroblastic reticular cells (FRC) upregulate expression of anti-apoptotic molecules in T cells and thereby maintain cell survival in interphase. Second, interaction with low-affinity self-pMHC ligands on APCs during the immune response augments TCR signaling induced by high-affinity foreign p-MHC ligands, thereby resulting in strong T cell activation.

Figure 3

Possible mechanisms involved in conversion of naïve T cells to memory-phenotype cells under normal physiological conditions. A subset of memory-phenotype cells is activated, fast-dividing cells. The mechanisms shown are largely speculative.