CD28 Receptor function

The potent costimulatory activity of anti-CD28 mAbs was first recognized by Gmunder and Lesslauer and was later confirmed and studied by many others. Identification of CD80 and CD86 molecules as CD28 ligands has allowed a comparison of CD28 signaling through anti-CD28 mAbs versus the natural ligands. These studies show that CD28 clustering on the cell surface during cell-cell adhesion results in optimal stimulation, whereas soluble CD80-Ig or CD86-Ig fusion proteins are not effective. CD28 mAbs have activity in solution when they are bivalent or multivalent, but are less effective than CD80- or CD86-positive cells in activating the CD28 receptor. Optimal stimulation of the CD28 receptor therefore requires a high degree of receptor cross-linking or oligomerization.

CD28 signals depend on the activation of intracellular protein tyrosine kinases, including Ick and itk, resulting in direct phosphorylation of CD28 on tyrosine residues. After activation, CD28 associates with phosphatidylinositol 3-kinase (PI3K) by an SH2 interaction with phosphorylated Tyrl70. However, the association with PI3K is not essential for CD28 costimulatory function, and Tyrl88 plays a more important role. However, it is not yet clear how the CD28 cytoplasmic tail delivers costimulatory signals.

CD28-deficient mice have been generated and found to have an impaired immune system, with reduced responses to T cell mitogens and reduced ability to mount antibody responses to T-dependent antigens. In contrast, CTLA-4 deficient mice die at an early age of lymphoproliferative disease, demonstrating that CTLA-4 delivers inhibitory signals for T cell activation. CTLA-4 has been reported to associate with a tyrosine phosphatase, SYP, that is thought to inhibit the activation of tyrosine kinases or tyrosine kinase substrates during CD28 cross-linking.

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