Numerous transcription factors which control the differentiation, function, migration and survival of different classes of effector and memory T cells have been identified, but the precise functions of many of these transcription factors which regulate the outcome of an immune response are incompletely defined. KLF2, a member of the Kruppel-like factor family, has diverse roles in the immune system, and in particular plays a critical role in controlling migration of T (and B) cells via its control of expression of key homing receptors which determine selective trafficking capabilities. Other functions of KLF2 remain mostly undefined. A striking and unusual feature of KLF2 is its rapid loss of expression in T, B and multiple other cell types following cellular activation. Despite this feature of KLF2 being known for over two decades and efforts by several investigators, the physiologic importance of this loss of KLF2 remains poorly defined. We have generated a novel, powerful, and sophisticated mouse model which for the first time makes possible interrogation of the functions of KLF2 downregulation. In this model, loss of KLF2 expression is completely and permanently blocked in any cell type which expresses or which once expressed cre recombinase. We present extensive data showing that this novel mouse model has a normal peripheral T cell compartment prior to immunologic challenge, yet induction of CD8 T cell effectors in response to infection with LCMV Armstrong is sharply impaired. In addition, we unexpectedly found that expression of PD-1, a major inhibitory receptor which is an important marker of exhausted T cells and the primary target of checkpoint blockade therapy, is higher and far more sustained in CD8 T cells which cannot turn off KLF2 expression, compared to WT, despite the well established fact that LCMV Armstrong causes acute resolving infection and does not induce T cell exhaustion. We propose to explore the regulation and function of PD-1 in this novel mouse model.
In Aim 1, we will determine the role of PD-1 signaling in defective responses of K121R CD8 T cells.
In Aim 2, we will determine whether KLF2 maintains PD-1 expression via repression of Blimp-1. These studies will significantly advance our understanding of the functions of KLF2 and KLF2 downregulation in T cell responses.
Inflammatory diseases are often caused by a class of white blood cell termed T cells. How the various types of mature T cells function and respond to infectious pathogens is incompletely understood. This application focuses on why expression of a particular transcription factor called KLF2, which controls numerous aspects of the development, function, and migration of T cells, is shut off following the activation of T cells, using a novel mouse model in which expression of KLF2 cannot be turned off in T cells.
