Innate memory T cells

Abstract

Memory T cells are usually considered to be a feature of a successful immune response against a foreign antigen, and such cells can mediate potent immunity. However, in mice, alternative pathways have been described, through which naïve T cells can acquire the characteristics and functions of memory T cells without encountering specific foreign antigen or the typical signals required for conventional T cell differentiation. Such cells reflect a response to the internal rather the external environment, and hence such cells are called innate memory T cells. In this review, we describe how innate memory subsets were identified, the signals that induce their generation and their functional properties and potential role in the normal immune response. The existence of innate memory T cells in mice raises questions about whether parallel populations exist in humans, and we discuss the evidence for such populations during human T cell development and differentiation.

Keywords: CD8 T cells; Cytokines; Homeostasis; Immune memory; NKT cells.

Figure 1

Overview of generation pathways and characteristics of innate and conventional memory T cell populations. Naïve T cells can respond to a variety of endogenous and exogenous (or experimental) signals to produce memory-phenotype cells. Stimulation by foreign antigens, in a suitably immunogenic way, will produce “antigen-induced memory,” while there are two pathways that produce “Innate memory” T cells: these pathways involve the response to lymphopenia or the response to IL-4. Populations of T cells with innate memory properties are found in normal animals at steady state—these are termed virtual memory cells. Key factors involved in generation of these cells and major phenotypic characteristics that are shared or distinguished these different populations are indicated. More details in the text.

Figure 2

Key elements in generation of lymphopenia-induced memory T cells. Naïve T cells in a normal environment (left) are maintained through basal signals through IL-7R and TCR. The intensity of IL-7R signals (indicated by white stars) is limited both by competition between T cells for access to IL-7 and by the fact that IL-7 signals cause reduction in IL-7Rα expression. TCR signals induced by encounter with self-peptide/-MHC ligands are also important for naïve T cell survival. The intensity of TCR signals induced by self-ligand stimulation varies for different clones (indicated by green (light gray in the print version) lightning bolts), and this correlates directly with expression of the cell surface molecule CD5 (not shown). In a lymphopenic situation (right), both IL-7R and TCR signals are enhanced and/or maintained, leading some clones (red TCR (dark gray in the print version)) to proliferate and increase expression of transcription factors and cell surface markers associated with memory cells. Other clones, with weaker basal TCR signaling (and/or lower IL-7R expression—not shown), do not respond to these cues. Maintenance of lymphopenia-induced memory cells (at least for CD8+ T cells) involves stimulation through IL-15R, which can maintain basal proliferation after IL-7R signaling reverts to normal levels. Memory T cells do not require TCR engagement for survival.

Figure 3

Key elements in generation of IL-4-induced memory T cells. Developing thymocytes reaching the CD4+ or CD8+ SP stage respond to high levels of the cytokine IL-4 by upregulation of the transcription factor Eomes, and subsequent acquisition of memory-phenotype (MP) and memory-like functional properties. This effect is much more pronounced for CD8 than CD4 T cells. Cells expressing the transcription factor PLZF are the typical source of IL-4, and this population is comprised chiefly of a subset of iNKT cells (NKT2) or TCRγδ T cells with properties similar to NKT cells (γδNKT). This process may not exclusively initiate in the thymus, since some models show IL-4-induced memory CD8 T cells arise exclusively in the peripheral lymphoid tissues. It is currently unclear whether TCR signals cooperate with IL-4R stimulation in generation of IL-4-induced memory T cells. See Table 1 for more details of genetic manipulations that influence generation of IL-4-induced memory T cells.

Figure 4

Pathways involved in generation of iNKT subsets, including IL-4 producing NKT2 cells. The factors involved in generating the three distinct subsets of iNKT cells (NKT1, NKT2, and NKT17), and unique properties of those subsets, are indicated. TCR interactions with CD1d (bearing ill-defined self-glycolipid(s)) and homotypic Slam protein interactions leads CD4+CD8+ double positive (DP) thymocytes to upregulate the PLZF transcription factor and differentiate into immature NKT precursors (NKTp). In response to factors and induced transcription factors indicated, these cells differentiate into NKT1, NKT2, or NKT17 populations, bearing distinct phenotypic markers, levels of PLZF, and functional properties. The NKT2 population produces IL-4 at steady state and, if present in suitable numbers, can promote differentiation of IL-4-induced memory T cells in the thymus. This population naturally occurs in abundance in BALB/c strain mice, but is much more rare in C57BL/6 strain mice: these strain-specific differences may involve the relative expression of indicated factors.