T-cell antigen receptor (TCR) signalling is essential for the activation, proliferation, and effector function of T cells. While key steps in the activation of T cells are well-established, the precise molecular circuits downstream of TCR remain a subject of intense investigation. We set out to better characterize the role of a poorly understood MAP3 kinase, Thousand and one kinase 3 (TAOK3), in T cell homeostasis and antiviral responses.

Therefore, our lab generated a Taok3 deficient mouse model by means of CRISPR/Cas. Whereas early thymic development was favoured, Taok3-/- thymocytes were compromised beyond the double positive (DP) stage. However, a considerable amount of naïve T cells still made it to the periphery, and these cells expressed higher levels of CD5 and CD44, indicative of a higher degree of self-reactivity of the TCR repertoire, most likely needed to overcome any defects caused by the lack of TAOK3. Naïve cells were yet lost in the periphery due to defective homeostatic signalling and were unable to differentiate well into effector cells upon seeing foreign antigens. As measured using techniques such as alloMLR, and OVA-specific responses in vitro as well as antiviral responses against Pneumonia Virus of Mice (PVM) and SARS-CoV-2 in vivo. Employing a Nur77-eGFP reporter system, we were able to show that activated Taok3-/- T cells did probably not reach the threshold of accumulated TCR signalling to undergo proliferation.

With these preliminary results, we show that TAOK3 is specifically required for proper canonical TCR signalling, both during developmental stages in the thymus as well as during homeostatic survival and effector signalling in the periphery.