Regulation of CD4+ T cell responses by PTEN

Phosphoinositide-3 kinase (PI3K) is activated downstream of a number of receptors expressed on the surface of T cells, and its activation is critical for cell survival, proliferation, and chemotaxis. Originally identified as a tumor suppressor, the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a key negative regulator of PI3K signaling. We have used young mice with a T cell specific deficiency in PTEN (referred to as PTEN-DeltaT mice) to study the role that PTEN plays in regulating T cell activation. Initial studies revealed that in the absence of PTEN, TCR signals alone, without CD28 costimulation, are sufficient to induce hyperactivation of the PI3K pathway in naive CD4+ T cells. This enhanced responsiveness to sub-maximal TCR stimulation allows PTEN-DeltaT CD4+ T cells to proliferate and produce cytokines in the absence of costimulation both in vitro and in vivo. Importantly, PTEN-DeltaT CD4+ T cells, uncoupled from the requirement for CD28 costimulation, are refractory to anergy/tolerance induction. Together, these data support our hypothesis that negative regulation of TCR signals by PTEN plays a critical role in regulating T cell activation and tolerance induction by imposing a requirement for CD28 costimulation.;With age, PTEN-DeltaT mice develop both autoimmune disease as well as T cell lymphomas. This phenotype allowed us to ask additional questions about the relationship between autoimmunity and malignancy in vivo . A series of cell transfer experiments led us to hypothesize that mature peripheral T cells from young PTEN-DeltaT mice are not capable of transformation. Strikingly, thymectomy experiments confirmed this hypothesis and revealed that removal of the thymus from young PTEN-DeltaT mice completely prevents tumor formation. Interestingly, however, with age, thymectomized PTEN-DeltaT mice still develop autoimmune disease. These and other data suggest that separate mechanisms regulate autoimmunity and cancer in PTEN mutant mice and highlight a critical role for the thymus in uncoupling these two disease fates.