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Abstract
Certain disulfide bonds present in leucocyte membrane proteins are labile and can be reduced in inflammation. This can cause structural changes that result in downstream functional effects, for example, in integrin activation. Recent studies have shown that a wide range of membrane proteins have labile disulfide bonds including CD132, the common gamma chain of the receptors for several cytokines including interleukin-2 and interleukin-4 (IL-2 and IL-4). The Cys183–Cys232 disulfide bond in mouse CD132 is susceptible to reduction by enzymes such as thioredoxin (TRX), gamma interferon-inducible lysosomal thiolreductase and protein disulfide isomerase, which are commonly secreted during immune activation. The Cys183–Cys232 disulfide bond is also reduced in an in vivo lipopolysaccharide (LPS)-induced acute model of inflammation. Conditions that lead to the reduction of the Cys183–Cys232 disulfide bond in CD132 inhibit proliferation of an IL-2-dependent T cell clone and concomitant inhibition of the STAT-5 signalling pathway. The same reducing conditions had no effect on the proliferation of an IL-2-independent T cell clone, nor did they reduce disulfide bonds in IL-2 itself. We postulate that reduction of the Cys183–Cys232 disulfide in CD132 inhibits IL-2 binding to the receptor complex. Published data show that the Cys183–Cys232 disulfide bond is exposed at the surface of CD132 and in close contact with IL-2 and IL-4 in their respective receptor complexes. In addition, mutants in these Cys residues in human CD132 lead to immunodeficiency and loss of IL-2 binding. These results have wider implications for the regulation of cytokine receptors in general, as their activity can be modulated by a ‘redox regulator’ mechanism caused by the changes in the redox environment that occur during inflammation and activation of the immune system.
Highlights
Disulfide bonds are important in maintaining the structure of extracellular and secreted proteins, but it is apparent that some disulfide bonds are labile and their reduction leads to functional changes [1,2]
We have recently developed a proteomics-based technique to determine the membrane proteins of leucocytes that have labile disulfides using mild reducing conditions such as dilute tris(2-carboxyethyl)phosphine (TCEP), and enzymes such as TRX, gamma interferon-inducible lysosomal thiolreductase (GILT) and protein disulfide isomerase (PDI) that are commonly secreted during immune activation [20,21]
The CD132 chain was identified as containing a redox-labile disulfide bond (Cys183 – Cys232) in screens of T cells treated with the chemical reductant TCEP and three enzymatic reductants (TRX, GILT and PDI), and in spleen cells from mice treated with LPS in a short-term model of inflammation [20]
Summary
Disulfide bonds are important in maintaining the structure of extracellular and secreted proteins, but it is apparent that some disulfide bonds are labile and their reduction leads to functional changes [1,2]. Activation of T cells by dendritic cells leads to secretion of thioredoxin (TRX) into the extracellular space [16], where it can catalyse reduction of disulfide bonds on the surface of cells with which it comes into contact. In a model of arthritis, disease susceptibility was shown to correlate with the level of free thiols at the surface of T cells, and this was dependent on intracellular reactive oxygen levels [19], suggesting a role for redox chemistry in autoimmunity. Combined, these data suggest a central role for redox chemistry at the cell surface in controlling the levels of the immune response to antigen
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