Co-stimulatory signaling

Blotta, M.H., Marshall, J.D., De Kruyff, R.H. and Umetsu, D.T. (1996) Cross-linking of the CD40 ligand on human CD4+ T lymphocytes generates a co-stimulatory signal that upregulates IL-4 synthesis. Journal of Immunology 156, 3133-3140. 

Selective costimulation modulator, inhibits T cell activation by binding to CD80 and CD86, thereby blocking the interaction of CD28 Activation provides a co-stimulatory signal necessary for full activation of T cells... 

IV. EXPOSITION OF AUTOANTIGENS AND INTERFERENCE WITH CO-STIMULATORY SIGNALS... 

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. 

Those cytokines which are generally permissive or inhibitory for antibody production by B lymphocytes and may influence the secretion of a number of different antibody isotypes, depending on which of the specific stimuli are present. These cytokines include IL-2, IL-5, IL-6 and IFN7 (but this is not an exhaustive list). Permissive stimuli other than cytokines, for example the co-stimulatory signals delivered by T lymphocytes, may also be included in this category. 

Jenkins, M.K., Burrell, E. and Ashwell, J.D. (1990). Ant en presentation by resting B cells. Effectiveness at inducing T cell proliferation is determined by co-stimulatory signals, not T cell receptor occupancy. J. Immunol. 144, 1585-1590. 

CD28 delivers a co-stimulatory signal involved in ant n-specific IL-2 production by human T cells. J. Immunol. 147, 2461-2466. 

Cytokine Production/Cellular Activation TNFa and IFNy mediate the induction of other cytokines (IL-1 and IL-6) and the activation of phagocytes. It has been suggested that particle-induced expression of MIP-2 and cytokine-induced neutrophil chemoattractant CKs in the rat lung are mediated at least in part by production of TNFa. TNF is involved in control of monocyte-mediated regulation of cytokine production by T cells. Preincubation of monocytes with rTNF enhanced their ability to induce IFNy production, and TNF synthesis inhibitors decreased this induction. However, Th2 cells are stimulated in the relative absence of monocyte co-stimulatory signal(s), probably IL-6. Concerning pain responsivity, TNFa produces dose-dependent hyperalgesia mediated via the induced release of IL-lp. ... 

Factors such as these translate into practical limitations. Typically, excessively high concentrations of bispecific antibody are needed to see an effect in vivo. In addition, particularly in solid tumors, the effector cells are often ineffective in the absence of a local co-stimulatory signal, which usually requires the addition of an exogenous factor, a serious drawback for a viable therapeutic strategy. 

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