Expression and Function of Tob in T Lymphocytes

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Cellular quiescence is a state characterized by decreased cell size and metabolic activity. Quiescence in naive lymphocytes acts to reduce the resources, energy and space, required to maintain a vast repertoire of T and B cells. Quiescence might also protect cells from accumulating metabolic damage that could result in malignancy. Recent studies have shown that quiescence in lymphocytes is an actively maintained rather than a default state in the absence of a signal. Quiescence factors identified to date, represent potential tumor suppressor genes because alterations in their expression or function contributes to progression of lymphoid malignancies. Thus, strategies to understand and enforce lymphocyte quiescence might be useful in controlling leukemia and lymphoma. Recently, we identified Tob as a gene that mediates quiescence in T lymphocytes. Our studies showed that Tob mRNA is highly expressed in anergic cells. Tob mRNA is also constitutively expressed in unstimulated, primary, peripheral blood T lymphocytes and is downregulated during activation via TCR/CD3 in the presence of costimulation. Forced expression of Tob inhibits transcription of cytokines and cyclins and T cell proliferation. In contrast, suppression of Tob with antisense oligonucleotide augments CDS-mediated responses and abrogates the requirement of costimulation for maximal proliferation and cytokine secretion. In order to understand the functional role of Tob in the immune response of the intact host, we have generated transgenic mice, which constitutively express Tob in their T cells. In vitro, Tob-Tg T cells display reduced proliferation and cytokine production. After in vivo immunization, Tob-transgenic mice display reduced primary responses and abrogated recall T cells responses to antigenic challenge. These results provide evidence that T cell quiescence is not a default state, but an actively maintained gene program that must be suppressed for T cell activation to occur. Our findings indicate that Tob has a critical role in maintaining T cell quiescence. Thus, understanding the biochemistry and logic behind the integrative processes that control Tob expression will illuminate drug targets and approaches to better regulate T cell immune responses either for immunosuppression in autoimmunity, transplantation and allergy or for augmentation in vaccines, chronic infections and cancer. Because Tob represents a potential tumor suppressor and Tob deficient mice develop malignant lymphomas, such studies might also provide insights to the pathophysiology of lymphoid malignancies. Thus, strategies to regulate Tob expression might be useful in controlling leukemia and lymphoma. To achieve these objectives I propose three specific aims to: 1) Determine the mechanisms that regulate Tob mRNA expression; 2) Determine the biochemical signaling pathways involved in transcriptional and post-translational regulation of Tob; 3) Determine the role of Tob in regulating T cell immune responses in the intact host, by using transgenic mice for Tob.