Cutting edge: T cell requirement for CD28 costimulation is due to negative regulation of TCR signals by PTEN.
Recent studies suggest that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays a critical role in the maintenance of self-tolerance. Using T cell-specific PTEN knockout mice (PTENDeltaT), we have identified a novel mechanism by which PTEN regulates T cell tolerance. We found that TCR stimulation alone, without CD28 costimulation, is sufficient to induce hyperactivation of the PI3K pathway, which leads to enhanced IL-2 production by naive PTENDeltaT T cells. Importantly, as a result of this increased response to TCR stimulation, PTENDeltaT CD4(+) T cells no longer require CD28 costimulation for in vitro or in vivo expansion. In fact, unlike wild-type T cells, PTENDeltaT CD4(+) T cells are not anergized by delivery of TCR stimulation alone. These data suggest that by negatively regulating TCR signals, PTEN imposes a requirement for CD28 costimulation, thus defining a novel mechanism for its role in self-tolerance.
Buckler
Jodi L
JL
Department of Medicine, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104-6144, USA.
Walsh
Patrick T
PT
Porrett
Paige M
PM
Choi
Yongwon
Y
Turka
Laurence A
LA
D000818:Animals; D015153:Blotting, Western; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D018106:CD28 Antigens; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse