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| Item Type: | Article |
|---|---|
| Title: | A cellular platform for the evaluation of immune checkpoint molecules |
| Creators Name: | Jutz, S., Hennig, A., Paster, W., Asrak, Ö., Dijanovic, D., Kellner, F., Pickl, W.F., Huppa, J.B., Leitner, J. and Steinberger, P. |
| Abstract: | Blockade of the T cell coinhibitory molecules CTLA-4 and PD-1 has clinical utility to strengthen T cell responses. In addition to these immune checkpoints an ever-growing number of molecules has been implicated in generating coinhibitory signals in T cells. However, investigating coinhibitory molecules in primary human cells is complicated by the restricted expression and promiscuity of both coinhibitory receptors and their ligands. Here we have evaluated the potential of fluorescence-based transcriptional reporters based on the human Jurkat T cell line in conjunction with engineered T cell stimulator cell lines for investigating coinhibitory pathways. CTLA-4, PD-1, TIGIT, BTLA and 2B4 expressing reporter cells were generated and activated with T cell stimulator cells expressing cognate ligands of these molecules. All accessory molecules tested were functional in our reporter system. Engagement of CTLA-4, PD-1, BTLA and TIGIT by their ligands significantly inhibited T cell activation, whereas binding of 2B4 by CD48 resulted in enhanced responses. Mutational analysis revealed intracellular motifs that are responsible for BTLA mediated T cell inhibition and demonstrates potent reporter inhibition by CTLA-4 independent of cytoplasmic signaling motifs. Moreover, considerably higher IC50 values were measured for the CTLA-4 blocker Ipilimumab compared to the PD-1 antibody Nivolumab. Our findings show that coinhibitory pathways can be evaluated in Jurkat-based transcriptional reporters and yield novel insights on their function. Results obtained from this robust reductionist system can complement more time consuming and complex studies of such pathways in primary T cells. |
| Keywords: | T Cell Activation, NF-kB, Reporter Cell Lines, Jurkat, Immune Checkpoints |
| Source: | Oncotarget |
| ISSN: | 1949-2553 |
| Publisher: | Impact Journals |
| Volume: | 8 |
| Number: | 39 |
| Page Range: | 64892-64906 |
| Date: | 12 September 2017 |
| Official Publication: | https://doi.org/10.18632/oncotarget.17615 |
| PubMed: | View item in PubMed |
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