Antigen recognition by the T-cell receptor induces the synthesis or activation of the transcription factors NFAT, AP-1, and NFκB, which bind to the promoter region of the IL-2 gene in naive T cells to activate its transcription (see Sections 7-14 and 7-16). Co-stimulation through CD28 contributes to the production of IL-2 in at least three ways. First, CD28 signaling activates PI 3-kinase, which increases production of the AP-1 and NFκB transcription factors, thereby increasing the transcription of IL-2 mRNA. However, the mRNAs of many cytokines, including IL-2, are very short-lived because of an ‘instability’ sequence (AUUUAUUUA) in the 3' untranslated region. CD28 signaling prolongs the lifetime of an IL-2 mRNA molecule by inducing the expression of proteins that block the activity of the instability sequence, resulting in increased translation and more IL-2 protein. Finally, PI 3-kinase helps activate the protein kinase Akt (see Section 7-17), which generally promotes cell growth and survival, increasing the total production of IL-2 by activated T cells.
9-17 Additional co-stimulatory pathways are involved in T-cell activation.
Once a naive T cell is activated, it expresses a number of proteins in addition to CD28 that contribute to sustaining or modifying the co-stimulatory signal. These other co-stimulatory receptors generally belong to either the CD28 or the TNF receptor family.
CD28-related proteins are expressed on activated T cells and modify the co-stimulatory signal as the T-cell response develops. One such protein is the inducible co-stimulator (ICOS), which binds a ligand known as ICOSL (ICOS ligand, or B7-H2), a structural relative of B7.1 and B7.2. ICOSL is produced on activated dendritic cells, monocytes, and B cells. Although ICOS resembles CD28 in driving T-cell proliferation, it does not induce IL-2 but seems to regulate the expression of other cytokines, such as IL-4 and IFN-γ, made by CD4 T-cell subsets. ICOS is particularly important for enabling CD4 T cells to function as helper cells for B-cell responses such as isotype switching. ICOS is expressed on T cells in germinal centers within lymphoid follicles, and mice lacking ICOS fail to develop germinal centers and have severely diminished antibody responses.
Another receptor for B7 molecules is CTLA-4 (CD152), which is related in sequence to CD28. CTLA-4 binds B7 molecules about 20 times more avidly
Fig. 9.24 Activated T cells secrete and respond to IL-2. activation of naive T cells induces the expression and secretion of IL-2 and the expression of high-affinity IL-2 receptors. IL-2 binds to the high-affinity IL-2 receptors to enhance T-cell growth and differentiation.
CTLA-4 binds B7 more avidly than does CD28 and delivers inhibitory signals to activated T cells activated T cell antigen-presenting cell MHC class II CD4 + TCRCTLA-4 B7.1
Fig. 9.25 CTLA-4 is an inhibitory receptor for B7 molecules. naive T cells express Cd28, which delivers a co-stimulatory signal on binding B7 molecules (see Fig. 9.22), thereby driving the survival and expansion of the T cells. activated T cells express increased levels of CTLa-4 (Cd152), which has a higher affinity than Cd28 for B7 molecules and thus binds most or all of the B7 molecules. CTLa-4 thereby serves to regulate the proliferative phase of the T-cell response.