Numerous cytokines play critical roles in adaptive immune responses. CD4+ helper T cells make the largest amount and variety of these cytokines, but some are also produced by CD8+ T cells and APCs. Cytokines secreted by DCs and other APCs are especially important for the differentiation of naive T cells into different types of effector cells. Various cytokines are involved in the proliferation and differentiation of antigen stimulated T cells and in the effector functions of these cells. Most of these cytokines act on nearby cells (paracrine action) or the cells that produce them (autocrine action). Cytokines that activate T cells work in concert with antigens and costimulation and are sometimes referred to as “signal 3.”
The roles of cytokines in the effector functions of T cells are described in Chapters 10 and 11. Here we discuss IL-2, a cytokine involved in early steps of T-cell responses.
Interleukin-2 Secretion and Interleukin-2 Receptor Expression
IL-2 is a growth, survival, and differentiation factor for T lymphocytes that plays a major role in the proliferation of anti gen-stimulated T cells and in the maintenance of functional regulatory T cells. IL-2 functions as an autocrine and paracrine cytokine.
IL-2 is produced mainly by CD4+ T lymphocytes activated by antigen and costimulators. Activation of these cells stimulates transcription of the IL2 gene and synthesis and secretion of the protein. IL-2 production is rapid and transient, starting within 1 to 2 hours after antigen recognition, peaking at about 8 to 12 hours, and declining by 24 hours. Secreted IL-2 is a 14- to 17-kD globular glycoprotein containing four α helices. It is the prototype of the four-α-helical cytokine family that interacts with type I cytokine receptors.
The high-affinity IL-2 receptor (IL-2R) is transiently expressed on activation of naive and effector T cells; regulatory T cells always express this receptor. The IL-2R consists of three noncovalently associated proteins: IL-2Rα (CD25), IL-2/15Rβ (CD122), and γc (CD132, also called IL-2Rγ) (Fig. 1). Of the three chains, only IL-2Rα is unique to the IL-2R. The β chain is also part of the IL-15 receptor, and the γ chain is shared with a number of cytokine receptors, including those for IL-4, IL-7, IL-9, IL-15, and IL-21, and is therefore called the common γ chain (γc). Both the β and γc chains engage JAK (Janus kinase)-STAT (signal transducers and activators of transcription) signaling pathways.
Fig1. The interleukin-2 receptor (IL-2R). (A) The structure of IL-2 bound to its trimeric receptor. (B) Different combinations of IL-2R chains are expressed on different cell types and bind IL-2 with different affinities. The cellular response to IL-2 is determined by which chains of the receptor are expressed. (The IL-2Rα chain is not expressed in isolation but is shown to indicate its binding affinity.) NK, Natural killer; Tregs, regulatory T cells. (A, Courtesy Drs. Kevin Jude and Chris Garcia, Stanford University. B, Modified from Spolski R, Li P, Leonard WJ. Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat Rev Immunol. 2018;18:648–659.)
IL-2Rβγc complexes are expressed at low levels on resting T cells (and on NK cells) and bind IL-2 with a Kd (equilibrium dissociation constant, a measure of binding affinity) of approximately 10−9 M. Expression of IL-2Rα and, to a lesser extent, of IL-2Rβ is increased on activation of naive CD4+ and CD8+ T cells (Fig. 2). The α chain associates with the βγc complex to form the complete IL-2R, the IL-2Rαβγc complex, which can bind IL-2 more tightly, with a Kd of approximately 10−11 M. Growth stimulation of activated T cells occurs at a similarly low IL-2 concentration. Because both IL-2 secretion and IL-2Rα production occur in response to antigen stimulation, the antigen-activated T cells are the ones that proliferate preferentially in response to the cytokine, compared with bystander cells that have not recognized the antigen. IL-2, produced in response to antigen stimulation, is itself a stimulus for induction of IL-2Rα, providing a feedback mechanism by which T-cell responses amplify themselves. Activated T cells express IL-2Rα transiently, long enough to respond to the growth factor and proliferate. CD4+ regulatory T cells constitutively express the complete IL-2R complex and require IL-2 for their maintenance, as discussed later and in Chapter 15. Chronic T-cell stimulation leads to shedding of the extracellular domain of IL-2Rα, and an increased level of shed IL-2Rα ectodomain in the serum is a marker of strong antigenic stimulation (e.g., acute rejection of a transplanted organ) and lymphoid malignancies.
Fig2. Regulation of interleukin-2 receptor (IL-2R) expression. Resting (naive) T lymphocytes express the IL-2Rβγc complex, which has a moderate affinity for IL-2. Activation of the T cells by antigen, costimulators, and IL-2 itself leads to expression of the IL-2Rα chain (also called CD25) and increased levels of the high-affinity IL-2Rαβγc complex. Regulatory T cells constitutively express the high-affinity IL-2Rαβγc com plex. APC, Antigen-presenting cell.
Functions of Interleukin-2
The biology of IL-2 is fascinating because it plays critical roles in both promoting and controlling T-cell responses and functions (Fig. 3).
• IL-2 stimulates the survival, proliferation, and differentiation of antigen-activated T cells. IL-2 promotes survival of cells by inducing the anti-apoptotic protein BCL-2. It stimulates cell cycle progression through activation of mTOR (mammalian target of rapamycin, also called molecular or mechanistic target of rapamycin), which induces the synthesis of cyclins and relieves a block in cell cycle progression through degradation of the cell cycle inhibitor p27. In addition, IL-2 increases production of effector cytokines, such as IFN-γ and IL-4, by T cells.
• IL-2 is required for the survival and function of regulatory T cells, which suppress immune responses against self and other antigens. These cells constitutively express the complete IL-2 receptor, including the α chain CD25, and are more sensitive to IL-2 than are activated and effector T cells. We will dis cuss this role of IL-2 in more detail in Chapter 15, when we describe the properties and functions of regulatory T cells. An interesting feature of this function of IL-2 is that regulatory T cells do not produce the cytokine, so they depend on IL-2 made by other T cells responding to antigens (see Fig. 3B).
Fig3. Biologic actions of interleukin-2 (IL-2). (A) IL-2 stimulates the survival, proliferation, and differentiation of T lymphocytes, acting as an autocrine growth factor, leading to the generation of effector and memory cells. (B) IL-2 also promotes the survival of regulatory T cells and maintains their functional capability, and thus controls immune responses (e.g., against self antigens). TCR, T-cell receptor.
