TIP, a T-cell factor identified using high-throughput screening increases survival in a graft-versus-host disease model

Abstract

A coordinated effort combining bioinformatic tools with high-throughput cell-based screening assays was implemented to identify novel factors involved in T-cell biology. We generated a unique library of cDNAs encoding predicted secreted and transmembrane domain–containing proteins generated by analyzing the Human Genome Sciences cDNA database with a combination of two algorithms that predict signal peptides. Supernatants from mammalian cells transiently transfected with this library were incubated with primary T cells and T-cell lines in several high-throughput assays. Here we describe the discovery of a T cell factor, TIP (T cell immunomodulatory protein), which does not show any homology to proteins with known function. Treatment of primary human and murine T cells with TIP in vitro resulted in the secretion of IFN-γ, TNF-α, and IL-10, whereas in vivo TIP had a protective effect in a mouse acute graft-versus-host disease (GVHD) model. Therefore, combining functional genomics with high-throughput cell-based screening is a valuable and efficient approach to identifying immunomodulatory activities for novel proteins.

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Figure 1
Figure 2: Examples of high-throughput screening assay for the T-cell program.
Figure 3: TIP: a T-cell immunomodulatory protein.
Figure 4: TIP induces cytokine secretion in primary human and murine T cells.
Figure 5: TIP induces MAPK activation and has a protective effect in an acute GVHD model in vivo.

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Acknowledgements

The authors wish to thank Andrea Smith for assistance with the manuscript preparation.

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Correspondence to Thi-Sau Migone.

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The authors declare no competing financial interests.

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Fiscella, M., Perry, J., Teng, B. et al. TIP, a T-cell factor identified using high-throughput screening increases survival in a graft-versus-host disease model. Nat Biotechnol 21, 302–307 (2003). https://doi.org/10.1038/nbt797

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