The IL2R Is One of the Most Thoroughly Studied Cytokine Receptors

Because of the central role of IL-2 and its receptor in the clonal proliferation of T cells, the IL-2 receptor has received intensive study. As noted in the previous section, the complete trimeric receptor comprises three distinct subunits— the a, p, and y chains. The p and y chains belong to the class I cytokine receptor family, containing the characteristic CCCC and WSXWS motifs, whereas the a chain has a quite different structure and is not a member of this receptor family (see Figure 12-7c).

The IL-2 receptor occurs in three forms that exhibit different affinities for IL-2: the low-affinity monomeric IL-2Ra, the intermediate-affinity dimeric IL-2Rpy, and the high-affinity trimeric IL-2Rapy (Figure 12-9). Because the a chain is expressed only by activated T cells, it is often referred to as the TAC (T-cell activation) antigen. A monoclonal anti-

receptors a a a

Exterior

Membrane

Interior

High-affinity (Q receptors

Same signal from all three

FIGURE 12-:

Interactions between cytokine-specific subunits and a common signal-transducing subunit of cytokine receptors. (a) Schematic diagram of the low-affinity and high-affinity receptors for IL-3, IL-5, and GM-CSF. The cytokine-specific subunits exhibit low-affinity binding and cannot transduce an activation signal. Noncovalent association of each subunit with a common p subunit yields a high-affinity dimeric receptor that can transduce a signal across the membrane. (b) Association of cytokine-specific subunits with a common signaling unit, the P subunit, allows the generation of cytokine-specific signals despite the generation of the same signal by the different cytokine receptors shown. (c) Competition of ligand-binding chains of different receptors for a common subunit can produce antagonistic effects between cytokines. Here binding of IL-3 by a subunits of the IL-3 receptor allows them to out-compete a chains of the GM-CSF receptor for p subunits. [Part (a) adapted from T. Kishimoto et al, 1992, Science 258:593.]

Intermediate affinity IL-2R

High affinity IL-2R

Low affinity IL-2R

Intermediate affinity IL-2R

High affinity IL-2R

Low affinity IL-2R

Y U

Y

ß

ß

Subunit

composition:

IL-2Rß

IL-2Ra

IL-2Ra

IL-2Ry

IL-2Rß

IL-2Ry

Affinity

constant (Ki):

107M

10nM

108M

Dissociation

constant (Kf):

10-9M

10-11M

10-8 M

Cells

-y-'

expressed by:

NK cells

Activated CD4+

and CD8+ T cells

Resting T cells

Activated B cells

(low numbers)

(low numbers)

1 FIGURE 12-9 1

Comparison of the three forms of the IL-2 receptor.

Signal transduction is mediated by the p and 7 chains, but all three chains are required for high-affinity binding of IL-2.

Signal transduction is mediated by the p and 7 chains, but all three chains are required for high-affinity binding of IL-2.

body, designated anti-TAC, which binds to the 55-kDa a chain, is often used to identify IL-2Ra on cells. Signal transduction by the IL-2 receptor requires both the p and 7 chains, but only the trimeric receptor containing the a chain as well binds IL-2 with high affinity. Although the 7 chain appears to be constitutively expressed on most lymphoid cells, expression of the a and p chains is more restricted and is markedly enhanced after antigen has activated resting lymphocytes. This phenomenon ensures that only antigen-activated CD4+ and CD8+ T cells will express the high-affinity IL-2 receptor and proliferate in response to physiologic levels of IL-2. Activated T cells express approximately 5 X 103 high-affinity receptors and ten times as many low-affinity receptors. NK cells express the p and 7 subunits con-stitutively, accounting for their ability to bind IL-2 with an intermediate affinity and to be activated by IL-2.

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