Tax Manipulation of Antigen Dependent TCell Activation

CD4+ T cells become activated when they recognize antigenic peptide fragments in concert with major histocompatibility complex (MHC) molecules expressed on antigen-presenting cells (APCs).49 APCs must also express the costimulatory molecule B7, which binds to CD28 on the T-cell surface, to transduce a strong activation signal. Cell surface recognition events trigger a signaling cascade via the TCR and B7, the ultimate result of which is to produce nuclear activators that can trans-activate the IL-2 gene.50 Tax has the ability to bypass the dependence on antigen recognition and activate this pathway, resulting in constitutive expression of IL-2.

HTLV-infected cells are anergic in the sense that they are unresponsive to antigen recognition. Expression of Rex inhibits the splicing of transcripts of the Src and Syk family kinases, resulting in the expression of FynB and Lyn rather than Lyk and Fyn.51

Figure 12-8. The effect of HTLV-1 accessory proteins on the antigen-dependent T-cell activation pathway. T-cell activation is triggered by antigen and co-stimulatory molecule recognition. These events trigger two pathways that result in the synthesis of nuclear activators responsible for the expression of the IL-2 gene. The calcium-dependent pathway involves production of inositol tris-phosphate (IP3), which opens calcium gated ion channels, resulting in a considerable calcium influx. Calcium ions bind to calmodulin, rendering it capable of activating calcineurin, which subsequently turns on the nuclear factor of activated T cells (NF-AT), a potent transcriptional activator. The calcium-independent pathway relies on recruitment of a small G protein (Ras), which activates a MAP kinase cascade and, along with a similar cascade transduced through the co-stimulatory molecule CD28, results in the synthesis of AP-1, another potent transcriptional activator.

HTLV-1-infected T cells are rendered anergic by the activity of the Rex protein, a known inhibitor of mRNA splicing. The presence of Rex inhibits the splicing of transcripts of the Src and Syk family kinases, resulting in the expression of FynB and Lyn rather than Lyk and Fyn (1). FynB and Lyn are far less active in the cell than the normal proteins, and do not respond well to receptor aggregation. Along with Tax-mediated trans-suppression of Zap-70, and trans-activation of Syk (2), antigen recognition is decoupled with cell activation. The ultimate end of the pathway, the transcription of IL-2, can occur constitutively through the Tax-mediated activation of calcineurin (3), a serine/threonine phosphatase, which dephosphorylates NF-AT, which can then migrate to the nucleus, bind to the IL-2 enhancer, and activate transcription of the IL-2 growth factor. Tax can also trans-activate the gene for c-Fos (4), resulting in greater amounts of AP-1, another activator of IL-2 transcription. (Adapted from Schwartz,50 with permission.)

FynB and Lyn are far less active in the cell than the normal proteins, and do not respond well to receptor aggregation. Along with Tax-mediated trans-suppression of Zap-70, and trans-activation of Syk, antigen recognition is decoupled with cell activation.51

Constitutive expression of IL-2 in HTLV-1-infected cells occurs through the Tax-mediated activation of calcineurin, a serine/threonine phosphatase. Tax has been shown to activate calcineurin resulting in constitutive dephosphorylation and consequent activation of the nuclear factor of activated T cells (NF-AT).52 Activated NF-AT translocates to the nucleus where it binds to CD29 response elements and acts as a potent stimulator of IL-2 production.53 Tax can also activate IL-2 production by stimulating the transcription of AP-1 substituent and increasing the DNA binding capabilities of AP-1.54,55 The effects of Tax on antigen-dependent T-cell activation are summarized in Figure 12-8.

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