Fig. 1

Potential inhibitors of inappropriate costimulation in AITL. CD28 is a costimulatory molecule essential for proper T cell activation. CD80/CD86 binding initiates several intracellular signaling pathways via association of kinases and adaptor proteins to its cytoplasmic domains. These in turn activate several intracellular signaling pathways (e.g. PI3K/Akt/mTOR and Ras/Raf/MAPK/ERK) resulting in proliferation, activation and differentiation and protein synthesis. CTLA-4 is a co-inhibitory molecule mitigating T cell activation. In general, CTLA-4 inhibits T cell activation by three mechanisms: competition for ligand binding, diminution of intracellular signaling protein recruitment and direct inhibition of downstream signaling pathways. Both mutant CD28 and the CTLA4-CD28 fusion protein mediate inappropriate costimulation potentially driving proliferation of malignant cells in AITL. Various already approved drugs can potentially block inappropriate costimulation by preventing ligand-coreceptor interaction or inhibiting the PI3K/Akt/mTOR and Ras/Raf/MAPK/ERK signaling pathways. Red arrows: activation, Blue dots: inhibition