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Unravelling PIM kinase signal integration in the T cell response

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Mechanisms behind T cell responses provide clues for more effective therapies

Understanding the mechanisms underlying T cell function is paramount for immunotherapy design. Following a proteomics approach, European researchers investigated the role of specific proteins in T cell responses.

Health

T cells offer immune protection by killing virus-infected or cancerous cells. However, in autoimmune disease, T cells incorrectly target parts of the human body or are responsible for rejecting newly transplanted organs unless their function is suppressed. Understanding how T cells handle different signals is therefore central for the development of immunotherapies.

Synergy between PIM kinases and mTORC1 unveiled

With the support of the Marie Skłodowska-Curie programme, scientists of the PIM PROTEOMICS project worked under the hypothesis that to change a T cell response the signal transmission pathways inside the cells must be inhibited. “When T cells receive a signal, they change their protein composition so that they can multiply and mount an immune response,″ explains the research fellow Julia Marchingo. Work focused on the role of two types of signalling pathway proteins implicated in T cell immune responses –PIM kinases, and mTORC1. Both PIM kinases and mTORC1 have been identified as important regulators of cell division, survival and protein synthesis, known to also promote the killing function of T cells; however they are thought to control these processes independently of each other. Drugs that target mTORC1 suppress the T cell immune response during organ transplantation. However, inhibition of mTORC1 alone is not always effective and inhibition of PIM kinases at the same time has been suggested as a way to improve therapeutic effectiveness. “We wanted to investigate if PIM kinases synergise with mTORC1 to control T cell responses and how their coordinated activity regulates T cell division, survival and differentiation outcomes,″ continues Marchingo. This comprehensive exploration of the downstream pathways of these two molecules will provide insight into how signals combine to regulate T cell fate and may be manipulated in the context of immunotherapy or transplant rejection.

Experimental approach

Using cutting-edge quantitative proteomic technology, scientists investigated the protein content in normal and PIM kinase-deficient T cells. They observed that PIM kinase deletion had only a small, context-specific effect on T cell protein composition with no universal function in immune responses. To identify potential downstream overlap between PIM kinases and mTORC1, Marchingo compared the list of PIM kinase-regulated and mTORC1-regulated proteins. Contrary to other reports in the literature, there was almost no overlap between the protein lists in all the environmental conditions tested, indicating that PIM kinases and mTORC1 were not working synergistically in an immune response. Furthermore, after treating normal and PIM kinase-deficient T cells with an mTORC1 inhibitor, scientists didn’t find any cell proliferation differences. This suggested that PIM kinases and mTORC1 don’t work together to control the strength of the T cell response.

Impact of the study

Collectively, the PIM PROTEOMICS project has demonstrated that PIM kinases and mTORC1 don’t cooperate to control T cell function but seem to have distinct effects on the T cell response. This questions the rationale of combining PIM kinase and mTORC1 inhibitors as a combined immunosuppressive therapy with an important wider impact for clinical drug development. Marchingo sums up with the important conclusion of the research: “PIM kinase inhibitors are unlikely to be of therapeutic benefit for suppression of an anti-transplant T cell immune response as initially envisaged.″

Keywords

PIM PROTEOMICS, PIM kinase, mTORC1, T cell, inhibitor, proteomics, immunotherapy

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