T-cell activation genes

Van Snick, J., Houssiau, F., Proost, P., Van Damme, J., and Renauld, J. C. (1996) I-309/T cell activation gene 3 chemokine protects murine T cell lymphomas against dexamethasone induced apoptosis. J. Immunol. 157, 2570-2576. 

Cox MB, Cairns MJ, Gandhi KS et al (2010) MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood. PLoS One 5 el2132... 

Discovery and Biochemical Studies FK506 was isolated in the course of the search for immunosuppressant from Streptomyces tsukubaensis [1,2]. The structure was determined as shown in 1 [3]. FK506 inhibited mixed lymphocyte reaction, cytotoxic T-cell generation, and expression of early T-cell activation genes [2,4]. 

Toed, M. J., Matkovich, D. A., Collier, K. A., et al. (1989). The inununo-suppressant FK506 selectively inhibits expression of early T cell activation genes. J. Immunol., 143, 718-726. 

Van Snick J. I-309/T cell activation gene-3 chemokine protects murine T cell lymphomas against dexamethasone-induced apoptosis. J Immunol 1996 157(6) 2570-6. 

Kieffer TL, Finucane MM, Nettles RE, Quinn TC, Broman KW, Ray SC, Persaud D, SUiciano RF (2004) Genotypic analysis of HIV-1 drug resistance at the limit of detection virus production without evolution in treated adults with undetectable HIV loads. J Infect Dis 189(8) 1452-1465 Kinoshita S, Su L, Amano M, Timmerman LA, Kaneshima H, Nolan GP (1997) The T cell activation factor NF-ATc positively regulates HIV-1 replication and gene expression in T cells. Immunity 6(3) 235-244... 

Cyclosporine and tacrolimus belong to a class of immunosuppressants called the calcineurin inhibitors. These agents are considered by many to be the cornerstone of medical immunosuppression. The calcineurin inhibitors work by complexingwith cytoplasmic proteins (cyclosporine with cyclophylin and tacrolimus with FK binding protein 12). These complexes then inhibit calcineurin phosphatase, which results in reduced IL-2 gene transcription. The final outcome is a decrease in IL-2 synthesis and a subsequent reduction in T cell activation.7 11 20 21... 

Table 14.1 IL-2 reporter gene assay (transfected Jurkat T cells) activity of pateamine A and derivatives... 

As explained, the immimomodulation signal starts with binding the antigen on T-cell receptor, which ultimately results in Ca2+ release. Ca2+ induces calmodulin activation, which in turn activates calcineurin, a Ca2+-dependent phosphatase. This event leads to translocation of the cytoplasmic component of the transcription factor, which is required for IL-2 gene expression and T-cell activation. 

Another class of transcription-modulating drugs is the immunosuppressants such as cyclosporin A (CsA), which inhibit T cell activation and proliferation, events playing a central role in the immune response and therefore in the inflammatory process. CsA blocks transcriptional induction of cytokines by inhibiting the phosphatase calcineurin, and by the subsequent inhibition of the activation of NF-AT and NF-AT-dependent activation genes. 

Tacrolimus suppresses peptidyl-prolyl isomerase activity by binding to the immuno-philin FK506-binding protein-12 (FKBP-12), and the tacrolimus-FKBP-12 complex binds to calcineurin and inhibits calcineurin phosphatase activity. As a result, calcineurin is unable to dephosphorylate NFATc and thus its migration to nucleus is blocked where its association with NFATn is necessary for the activation of key cytokine genes. Therefore, its mechanism of action is similar to cyclosporine although tacrolimus binds to a separate set of immunophilins in the cytoplasm. Tacrolimus, like cyclosporine, inhibits the secretion of key cytokines and inhibits T-cell activation (Fig. 4.2). 

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