Naive and memory T cells are maintained long term in a resting state, poised for reactivity to foreign antigen/self MHC ligands. Naive T cell survival is thought to involve stimulation by certain cytokines and induction of low grade signals from TCR encounter with self peptide/MHC ligands. Furthermore, some studies suggest TCR-self peptide/MHC interactions are critical for both naive and memory T cell function, in the model that encounter with self MHC ligands potentiates the response to foreign ligands. These features have fundamental significance for the """"""""self-awareness"""""""" of the T cell pool, and the function of thymic positive selection (the stage at which self MHC restriction is imparted on developing thymocytes). However, there are several contradictory studies in this field, such that the significance of TCR-self MHC interactions is highly controversial. This uncertainty is especially prominent in the case of CD8 T cells, and at present it is unclear whether and what role TCR binding to self Class I MHC molecules plays in naive or memory CD8 T cell survival and/or function. In other work, we have extensively studied the transcription factor KLF2 (also called LKLF), which was proposed to play a key function in T cell homeostasis. KLF2 deficient T cells develop in the thymus, but T cells are scarce in peripheral tissues, leading to the model that KLF2 regulates T cell survival. In contrast, our preliminary data indicate KLF2 regulates expression of trafficking molecules critical for thymic emigration and peripheral migration. These radical changes in T cell trafficking are manifest at late stages of thymic development, and this may mask other roles of KLF2 in fully mature T cells. Thus the role of this factor in mature T cell trafficking, survival and quiescence are still unresolved. In this competing continuation, we will test whether self peptide/MHC molecules are required for maintenance and/or function of naive CD8 T cells, and we will also explore the role of KLF2 in regulating mature T cell homeostasis.
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