Activation and Maturation of Lymphocytes

Inferleukin 2. IL-2 (or T-cell growth factor) is a 14- to 17-kDa glycosylated protein. Following antigen stimulation, IL-2 is synthesized in high concentrations by CD4 cells and in low concentrations by CD8 cells (Waldmann, 1993). Production is transient with peak activity occurring within 4 hr of activation. IL-2 acts on the same cells that synthesized the cytokine (autocrine effect) or on nearby T cells (paracrine effect). The IL-2 structure is common to a number of cytokines reacting with receptors having the WSXWS motif.

The IL-2 receptor is composed of two different proteins with differing affinities for IL-2. The IL-2Ra protein has a molecular mass of 75 kDa, reacts with the anti-TAC monoclonal antibody, has a low affinity (10 s M) for IL-2, and cannot initiate signal transduction. When IL-2RB protein is expressed alone, it does not bind IL-2 (Waldmann, 1993).

The addition of a third protein (IL-2Ry) to the IL-2Ra-IL-2Rp complex changes the conformation of the IL-2RB and increases the affinity constant for IL-2. Stabilization of the high-affinity unit may be facilitated by an additional 95-to 105-kDa protein (Waldmann and Goldman, 1989).

The IL-2Ry protein increases affinity constants in T and NK cells. Activated T cells expressing the a, B, and y proteins have a high affinity (1011 M) for IL-2. Large granular lymphocytes (NK cells) expressing only IL-2RB and IL-2Ry proteins have intermediate binding affinity (10-9 M) for IL-2 (Greene andLeonard, 1986).

IL-2 is important in the generation of an immune response. The concentration of IL-2 produced by Thl cells is directly related to the magnitude of the T-cell-mediated immune responses (Blazek and Mathe, 1983).

IL-2 also enhances the cytolytic activity ofNK cells creating lymphokine-activated killer (LAK) cells (Damle and Bradley, 1988). With respect to B cells, IL-2 acts both as a growth factor and as a stimulus for antibody production.

Interleukin 4. IL-4 is a monomelic 20-kDa peptide produced by CD4 Th2 lymphocytes, activated FceRI+ mast cells, basophils, and occasionally CD8 cells (Brown and Hural, 1997). It functions as a regulator of allergic reactions (Save-lkoul and van Ommen, 1996). Following stimulation with antigen, IL-4 serves as an autocrine growth factor for activated Th2 cells and a paracrine factor for the growth and differentiation of naive, antigen-stimulated Th2 cells (Duschl etal., 1995). Atthe same time, IL-4 induces isotypic switching inB cells that secrete only IgE antibodies.

There are effects on other cell targets. IL-4 increases the expression of adhesion molecules on vascular endothelial cells (VCAM-1) resulting in adhesion ofeosinophils, lymphocytes, and monocytes (Zurawski andde Vries, 1994). Also, IL-4 is a growth factor for mast cells.

Transforming Growth Factor. TGF-B is a small (28 kDa) cytokine produced in a latent form by T cells and monocytes. When acting as a cytokine, TGF-fl is a negative regulator that counteracts proinflammatory cytokines. It inhibits the proliferation of mitogen- or antigen-stimulated T cells. Also, TGF-fl inhibits the function and activation of macrophages, polymorphonuclear cells, and vascular endothelial cells.

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