Costimulatory signals

This is an immunoglobulin fusion protein with the cytotoxic lymphocyte antigen 4 (CTLA-4) receptor. By binding to CD80/86 on APCs it inhibits the CD28 costimulatory signal in lymphocytes. It is speculated that this can result in tolerance but up to now there is only experimental data [3,4]. 

Mueller, D. L., Jenkins, M. K., and Schwartz, R. H. (1989). Clonal expansion ver.sus functional clonal inactivation A costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu. Rev. Immunol. 7, 445-480. 

LPS can be directly mitogenic for T cells [130], but the antitumoral activity of lymphocytes depends on antigen recognition by their TCR in the context of the major histocompatibility complex (MHC) class I or n. Though LPS enhance it, T lymphocyte activity requires APC [131]. The effect of LPS on T lymphocytes has been shown to depend on monocytes independent of MHC, but to be due to the secretion of costimulatory signals and IL-12 in humans [132]. In vivo, LPS induces principally the proliferation of CD8+ T lymphocytes, but also that of CD4+ T and B lymphocytes through the activation of APC and secretion of IFN 0(7(3 in C57BL/6 mice [133],... 

Immunostimulatory adjuvants exert their effects predominantly at the cytokine level or through the activation of costimulatory signals. The type of response required for optimal protection depends on the pathogen. One class of immunostimulatory adjuvants is derived from the lipopolysaccharide of gram-negative bacteria. The most extensively evaluated member of this family, monophosphoryl lipid A (MPL), is obtained from Salmonella minnesota. MPL has been shown to induce the synthesis and release of cytokines, which promote the generation of specific immune responses. 

Wallich, R., Meuee, S. C. (1994). Costimulatory signals for human T-cell activation induce nuclear translocation of ppl9/cofilin. Proc. Natl. Acad. Sci. 

Experiments investigating co-stimulation have been based on the premise that TCR-mediated and costimulatory signals could be provided by ligands present on different surfaces. For example, the TCR-mediated signal could be provided to the T lymphocyte by anti-TCR antibody immobilized on a plastic surface and the co-stimulatory signal by any accessory cell of interest. This approach has been used (Mueller et a.1., 1989) to identify several features of the co-stimulatory signal. 

Aversa, G., Punnonen, J. and de Vries, J.E. (1993b). The 26-kD ttansmembrane form of tumor necrosis factor alpha on activated CD4 T cell clones provides a costimulatory signal for human B cell activation. J. Exp. Med. 177, 1575-1585. 

Blotta MH, Marshall JD, DeKruyff RH, Umetsu DT. Cross-linking of the CD40 hgand on human CD4 T lymphocytes generates a costimulatory signal that up-regulates IL-4 synthesis. J Immunol 1996 156 3133-40. 

Alefacept is a dimeric fusion protein that combines the first extracellular domain of human LFA-3 with the Ec portion of human IgGi. The LFA-3 segment of alefacept binds specifically to CD2 on T cells to prevent costimulatory signals delivered by LEA-3 and thereby inhibit cutaneous T-ceU activation and proliferation. Alefacept also induces selective apoptosis of memory-effector T cells and produces a dose-dependent decrease in circulating total lymphocytes. ... 

DCs that directly suppress the effector function of T cells mainly via secretion of IL-10 (b). Inhibited differentiation of immature DCs into fully functional proinflammatory DCs or redirection of mature DCs into an immature-like state prevents naive T cells from antigen-specific activation (c). Mature DCs providing incomplete costimulatory signals induce anergic or tolerant T cells (d). 

WEAVER, C.T., HAWRYLOWICZ, C.M. UNANUE, E.R. (1988) T helper cell subsets require the expression of distinct costimulatory signals by antigen-presenting cells. Proceedings of the National Academy of Sciences USA, 85, 8181-8185. 

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