Figure 1. Cytokines that modulate CD8⁺ T-cell homeostasis. (a) Naïve CD8⁺ cells depend primarily on low-level signals through contact with IL-7 and major histocompatibility complex class I molecules (MHC-I), which allow them to survive for extended periods with little or no proliferation. This survival is mediated through sustaining high (hi) levels of the anti-apoptotic protein Bcl-2. Naïve CD8⁺ cells also receive inhibitory signals by way of TGF-β. (b) When naïve CD8⁺ cells become activated by antigen (signal 1) plus costimulation (signal 2) they require a third signal through IL-12 or IFN-I for efficient expansion, effector functions and subsequent memory formation. High IL-12 production during this phase leads to upregulation of T-bet and downregulation of eomesodermin (Eomes), and also to upregulation of the anti-apoptotic protein Bcl-3, whereas Bcl-2 and IL-7Rα levels decrease upon TCR engagement. Following vigorous expansion, the majority of the effector T cells die by apoptosis during the contraction phase, leaving a small fraction (5–10%) of long-lived memory CD8⁺ cells. (c) Memory cells proliferate slowly in response to IL-15 and IL-7; this is facilitated through their expression levels of IL-2/15Rβ (CD122) and of IL-7Rα. IL-12 levels and, hence, T-bet and Eomes expression return to normal again; these latter two transcription factors in turn are responsible for maintaining high CD122 levels on CD8⁺ memory cells. For CD8⁺ memory cells, TGF-β inhibits proliferation whereas IFN-I can promote cell death in high concentrations but, via IL-15 production, might be stimulatory in low concentrations. Typical memory CD8⁺ cells that have a CD122^hi phenotype are MHC-I-independent, but a subset of CD122^lo memory CD8⁺ cells is MHC-I-dependent. The positive (+) and negative (−) influences mediated by cytokines under resting conditions or during an immune response are listed in the left column. Conversely, the right column shows ways to positively (+) modulate the respective CD8⁺ T-cell subset. For cytokines, their activity can be enhanced through association with anti-cytokine mAbs or, for IL-15, by binding to soluble recombinant IL-15Rα. Abbreviations: hi, high; int, intermediate; lo, low.

Figure 2. Cytokines that modulate CD4⁺ T-cell homeostasis. (a) Naïve CD4⁺ cells rely on signals through contact with IL-7 and major histocompatibility complex class II (MHC-II) molecules; such low-level stimulation does not induce proliferation but permits the cells to survive for extended periods. At this stage, CD4⁺ cells receive inhibitory TGF-β signals. (b) When naïve CD4⁺ cells become activated by antigen they downregulate IL-7Rα and undergo vigorous proliferation. This expansion is positively controlled by IFN-I and IFN-γ and is negatively influenced by the presence of IL-10 or administration of IL-2. As for CD8⁺ cells, most (90–95%) of the effector CD4⁺ cells subsequently disappear during the following contraction phase, giving rise to small numbers of long-lived memory CD4⁺ cells. (c) Memory cells depend on IL-7 and, to a lesser extent, on IL-15 for slow turnover and survival, which reflects their int/hi expression levels of CD122 and IL-7Rα; most although not all of these cells are MHC-II-independent. At the memory CD4⁺ stage, TGF-β plays a negative role in inhibiting T-bet-induced expression of CD122. The positive (+) and negative (−) influences mediated by cytokines under resting conditions or during an immune response are listed in the left column. The right column lists ways to modulate positively (+) the respective CD4⁺ T-cell subset. Abbreviations: hi, high; int, intermediate; lo, low.

Figure 3. Signals that lead to IL-15 production. Several cell types including antigen-presenting cells (APCs) produce and present IL-15 to T cells and NK cells. Signals by pathogen-associated molecular patterns (such as Poly I:C and lipopolysaccharide [LPS]) trigger specific Toll-like receptors (TLRs), which are expressed in high levels on APCs. Once activated, TLRs signal through the adaptor molecules Trif and MyD88, and induce production of inflammatory cytokines including IFN-I. IFN-I acts in an autocrine and paracrine fashion on APCs to activate the production of IL-15 and IL-15Rα in a STAT-1-dependent fashion. IL-15 and its receptor subunit assemble in intracellular compartments and are brought to the cell surface where they are presented in trans to CD122/γ_c-bearing cells, most notably CD8⁺ memory, NK and CD4⁺ memory cells. An alternative pathway leading to IL-15/IL-15Rα production and presentation is mediated through IL-12- and IL-18-induced IFN-γ secretion, which activates STAT-1 as well.