The immune response provides powerful protection against harmful infections. An important component of this response involves a cell type called a “T cell” which provides protection by killing virus infected cells or cancerous cells. However, in patients with autoimmune disease T cells can incorrectly target parts of the human body and cause disease. During organ transplantation T cells will also attack and lead to rejection of the newly transplanted organ unless their function is suppressed. Therefore, understanding how T cell responses can be reduced or switched off is of critical importance for designing drug therapies for treating autoimmune diseases or during organ transplantation.
In order for T cells to respond to a threat they must receive multiple external signals that indicate danger. These signals and transmitted internally by multiple pathways and cause the T cells to change their protein composition so that they can survive, multiply and develop the killing capability needed to form a strong immune response. One way that a T cell response can be switched off is to inhibit the internal transmission pathways from these signals so that T cells become unable to survive, multiply and kill. Therefore, understanding what these internal transmission pathways are and how they work together is of critical importance for designing immune suppressive therapies.
In this project I investigated how two types of signalling pathway proteins called the PIM kinases, and mTORC1 acted individually and together to control the strength and function of the T cell immune response.
PIM kinases have also been shown to play a role in supporting the T cell immune response, promoting T cell multiplication and survival. How the PIM kinases have this effect in T cells in not well understood. Drugs that inhibit the PIM kinases are in clinical development and testing. mTORC1 is known to promote cell growth and killing function in T cells. A drug inhibiting mTORC1 function is used clinically in order to suppress the T cell immune response during organ transplantation. Inhibition of mTORC1 alone is not always effective at suppressing the T cell immune response. Therefore, combining mTORC1 inhibition with other drugs, such as inhibitors of PIM kinases, to increase therapeutic effectiveness is of clinical interest. Previously, it was shown that removal of PIM kinases and inhibition of mTORC1 acts synergistically to prevent T cells from switching on and multiplying. How these two proteins work together to control T cell growth is not known.
The overarching goal of this project was to better understand what PIM kinases are doing in T cells and to explore how PIM kinases were synergising with mTORC1 to control the T cell response. In this context, the objectives of this project were:
1) To measure how removal of PIM kinases changed the protein composition of T cells
2) To look for overlaps in changes to T cell protein composition when PIM kinases have been removed or mTORC1 inhibited
3) Test the effect PIM kinase removal and inhibition of mTORC1 on the ability of T cells to multiply, survive and develop the killing capability necessary to form a strong and effective immune response.
