Antigen-specific T cell response in Tyk2-/-mice

The mechanisms underlying immunological tumour surveillance are not fully understood. We showed previously that TYK2-deficient animals, which are phenotypically normal unless exposed to excessive virus load, are more susceptible to tumours induced by the Abelson oncogene. This effect is due to impaired tumour surveillance in TYK2-/- mice and NK cells were shown to be important mediators therein. Given the role of TYK2 in interferon- and interleukin-12-dependent signalling, one might assume that TYK2-/- animals also display an impaired adaptive immune response. In fact, our preliminary data point to an additional role of TYK2 for antigen-specific T cell responses. Thus, the working hypothesis underlying this grant proposal is based on the observations that not only innate (e.g. NK-cell mediated tumour surveillance) but also the adaptive immune, i.e. antigen-specific, response is impaired in the absence of TYK2. Cellular adaptive immunity relies mainly on the activation of professional antigen presenting cells such as dendritic cells, their ability to prime T cells and finally the effector function of T cells. The defect of T cell function that we observed in the pilot study might therefore result from a defect in one or several phases of this process. Our aim is to identify the cellular compartment that is affected and, subsequently, to define the step(s) in this chain of events that are impaired by a combination of in vitro and in vivo experiments. The insights generated in this project are anticipated to have an impact on clinical medicine and on drug development; one can, for instance, envisage that one of the components of the signalling pathway may be an interesting target for achieving selective immunosuppression, e.g. for the prevention of transplant rejection.

The establishment of a tumour is a permanent battle between the transformed cells and the immune system. Key mediators in the recognition and eradication of tumour cells are natural killer (NK) cells, NKT cells and cytotoxic T lymphocytes (CTLs). However, the mechanisms underlying immunological tumour surveillance are not fully understood. We have observed in a previous study that animals deficient for the Janus kinase Tyk2 are prone to develop Abelson-induced B lymphoid leukaemia/lymphoma. The high susceptibility of Tyk2-/- mice to lymphoid tumours was the result of an impaired tumour surveillance rather than a tumour cell intrinsic effect. This defect in surveillance of B lymphoid leukaemia was due to a decreased cytotoxic capacity of Tyk2-deficient NK and NKT cells. In this study we have revealed that Tyk2 is also essential for T cell-mediated tumour surveillance. We demonstrated that Tyk2-/- mice are highly tumour-prone when challenged with tumour cells such as EL4 thymoma cells that are under the control of CTLs. In vitro and in vivo assays revealed a severe impairment of CD8 + T cell- mediated cytotoxicity upon Tyk2 deficiency. Tyk2 is important for the signalling downstream of type I interferon (IFN), interleukin-12 (IL-12) and IFN gamma. We could link the reduced CTL-dependent killing to impaired type I IFN signalling, whereas IFN gamma and IL-12 seem to be of minor importance, since we observed an impaired CTL activity only in mice deficient of the type I IFN receptor (IFNAR1) but not on IFN gamma or IL-12 deficiency. Our findings strengthen the concept that Tyk2 inhibition is a powerful therapeutic option for patients suffering from diseases linked to hyperactivation of the immune system or for patients undergoing transplantation.