Homeostasis of Naive and Memory T Lymphocytes

Abstract

Conventional CD4⁺ and CD8⁺ T lymphocytes comprise a mixture of naive and memory cells. Generation and survival of these T-cell subsets is under strict homeostatic control and reflects contact with self-major histocompatibility complex (MHC) and certain cytokines. Naive T cells arise in the thymus via T-cell receptor (TCR)-dependent positive selection to self-peptide/MHC complexes and are then maintained in the periphery through self-MHC interaction plus stimulation via interleukin-7 (IL-7). By contrast, memory T cells are largely MHC-independent for their survival but depend strongly on stimulation via cytokines. Whereas typical memory T cells are generated in response to foreign antigens, some arise spontaneously through contact of naive precursors with self-MHC ligands; we refer to these cells as memory-phenotype (MP) T cells. In this review, we discuss the generation and homeostasis of naive T cells and these two types of memory T cells, focusing on their relative interaction with MHC ligands and cytokines.

Figure 1.

Self-Ag recognition modulates T-cell receptor (TCR) sensitivity and cytokine reactivity in CD8⁺ T cells. Self-antigen (Ag) recognition promotes CD8⁺ T-cell survival, partly by enhancing interleukin-7 receptor (IL-7R) expression levels. Also, CD8⁺ T cells with strong reactivity to self-Ags have high levels of inhibitory CD5 and CD45 molecules and reduced expression of CD8. Altered expression of these molecules causes a reduction in TCR sensitivity as defined by short-term assays in vitro. However, despite reduced TCR sensitivity, CD5^hi cells show enhanced expression of lipid rafts, thereby leading to augmented responsiveness to cytokines, notably IL-2 and IL-15. For this reason, CD5^hi cells give stronger responses to Ags in vivo than CD5^lo cells. This applies both to homeostatic proliferation to self-Ags in lymphopenic hosts and typical responses to foreign Ags.

Figure 2.

Recognition of foreign (strong) versus self (weak) antigens (Ags) generates different outcomes. When naive T cells recognize foreign Ags in the presence of sufficient levels of costimulation and cytokines, they proliferate extensively to give rise to Ag-specific effector T cells. After pathogen clearance, most effector T cells die, while a small fraction of cells survives as Ag-specific memory T cells. On the other hand, when naive T cells recognize self-Ags, they undergo a relatively mild proliferative response; such homeostatic proliferation generates a population of cells with a memory phenotype (MP).

Figure 3.

Steady-state generation of memory-phenotype (MP) cells and their immunological functions during infection. CD4⁺ and CD8⁺ MP cells are homeostatically generated from naive precursors. Once generated, they engage in typical antigen (Ag)-specific immune responses to pathogens. In addition, they exert innate-like effector activity by responding to cytokines such as interleukin (IL)-2, IL-12, and IL-18 and by producing effector cytokines in the absence of cognate Ag recognition.