IL2 Secretion and IL2 Receptor Expression

Cytokines play critical roles in adaptive immune responses; in such responses, the major sources of cytokines are T cells, especially (but not exclusively) CD4+

helper T cells. The most important cytokine produced by T cells early after activation, often within 2 to 4 hours after recognition of antigen and costimulators, is interleukin-2 (IL-2), and this is described here. The cytokines secreted by effector cells are described in Chapter 10, when we discuss the functions of effector CD4+ T cells.

IL-2 is a growth, survival, and differentiation factor for T lymphocytes and plays a major role in the regulation of T cell responses by virtue of its crucial role in the maintenance of regulatory T cells. Because of its ability to support proliferation of antigen-stimulated T cells, IL-2 was originally called T cell growth factor (TCGF). It acts on the same cells that produce it or on adjacent cells (i.e., it functions as an autocrine or paracrine cytokine).

IL-2 is produced mainly by CD4+ T lymphocytes. Activation of T cells by antigens and costimulators stimulates transcription of the IL-2 gene and synthesis and secretion of the protein. IL-2 production is rapid and transient, starting within 2 to 3 hours of T cell activation, peaking at about 8 to 12 hours, and declining by 24 hours. CD4+ T cells secrete IL-2 into the immunologic synapse formed between the T cell and APC (see Chapter 7). IL-2 receptors on T cells also tend to localize to the synapse, so that the cytokine and its receptor reach sufficiently high local concentrations to initiate cellular responses.

Secreted IL-2 is a 14- to 17-kD glycoprotein that folds into a globular protein containing four a helices (Fig. 9-9). It is the prototype of the four-a-helical cytokines that interact with type I cytokine receptors (see Chapter 7).

Functional IL-2 receptors are transiently expressed on activation of naive and effector T cells; regulatory T cells always express IL-2 receptors. The IL-2 receptor (IL-2R) consists of three noncovalently associated proteins including IL-2Ra (CD25), IL-2/15RP (CD122), and yc (CD132). Of the three chains, only IL-2Ra is unique to the IL-2R. IL-2 binds to the a chain alone with low affinity, and this does not lead to any detectable cytoplasmic signaling or biologic response. IL-2/15RP, which is also part of the IL-15 receptor, contributes to IL-2 binding and engages JAK3-STAT5-dependent signal transduction pathways (see Chapter 7). The y 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 y chain (yc). Even though the yc is not directly involved in binding IL-2, its association with the receptor complex is required for high-affinity IL-2 binding and for full activation of signal transduction pathways. The IL-2RPyc complexes are expressed at low levels on resting T cells (and on NK cells) and bind IL-2 with a Kd of approximately 10-9 M (Fig. 9-10). Expression of IL-2Ra and, to a lesser extent, of IL-2RP is increased on activation of naive CD4+ and CD8+ T cells. Cells that express IL-2Ra and form IL-2RaPyc complexes can bind IL-2 more tightly, with a Kd of approximately 10-11 M, and growth stimulation of such cells occurs at a similarly low IL-2 concentration. IL-2, produced in response to antigen stimulation, is a stimulus for induction of IL-2Ra, providing a mechanism by which T cell responses amplify themselves. CD4+ regulatory T cells (see Chapter 14) express the full IL-2R complex and are thus poised to respond to

IL-2Ra

FIGURE 9-9 Structure of IL-2 and its receptor. The crystal structure of IL-2 and its trimeric receptor shows how the cytokine interacts with the three chains of to the receptor. (Reproduced from Wang X, M Rickert, and KC Garcia. Structure of the quaternary complex of interleukin-2 with its a, f and yc receptors. Science 310:1159-1163, 2005, with the permission of the publishers. Courtesy of Drs. Patrick Lupardus and K. Christopher Garcia, Stanford University School of Medicine, Palo Alto, California.)

FIGURE 9-9 Structure of IL-2 and its receptor. The crystal structure of IL-2 and its trimeric receptor shows how the cytokine interacts with the three chains of to the receptor. (Reproduced from Wang X, M Rickert, and KC Garcia. Structure of the quaternary complex of interleukin-2 with its a, f and yc receptors. Science 310:1159-1163, 2005, with the permission of the publishers. Courtesy of Drs. Patrick Lupardus and K. Christopher Garcia, Stanford University School of Medicine, Palo Alto, California.)

the cytokine. Chronic T cell stimulation leads to shedding of IL-2Ra, and an increased level of shed IL-2Ra in the serum is used clinically as a marker of strong antigenic stimulation (e.g., acute rejection of a transplanted organ).

Functions of IL-2

The biology of IL-2 is fascinating because it plays critical roles in both promoting and controlling T cell responses and functions (Fig. 9-11).

• IL-2 stimulates the survival, proliferation, and differentiation of antigen-activated T cells. IL-2 promotes survival of cells by inducing the antiapoptotic protein Bcl-2. It stimulates cell cycle progression through the synthesis of cyclins and relieves a block in cell cycle progression through p27 degradation. In addition, IL-2 increases production of effector cytokines, such as IFN-y and IL-4, by the T cells.

• IL-2 is required for the survival and function of regulatory T cells, which suppress immune responses against self and other antigens. In fact, knockout mice lacking IL-2 or IL-2 receptors develop uncontrolled T and B cell proliferation and autoimmune disease because of a defect in regulatory T cells. These studies indicate other growth factors can replace IL-2 for expansion of effector T cells, but that no other cytokine can replace IL-2 for the maintenance of functional regulatory T cells. We will discuss this role of IL-2 in more detail in Chapter 14, when we describe

T cell activation by antigen + costimulator

Secretion of IL-2

Expression of IL-2Ra chain; formation of high-affinity IL-2RaPy complex

IL-2RPyc complex

CD28 Resting Costimùlator ^ (naive) (B7) _ fl T cell

IL-2-induced T cell proliferation

IL-2RaPyc complex

IL-2RaPyc complex

FIGURE 9-10 Regulation of IL-2 receptor expression. Resting (naive) T lymphocytes express the IL-2R|3y 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-2Ra chain and high levels of the high-affinity IL-2Ra|3y complex.

Dendritic cell

Dendritic cell

Naive T cell

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