A connection between intrinsic negative regulation and survival is evident from the results described above regarding how Ian5-deficient T cells undergo apoptosis after they enter the peripheral circulation due to their progression to an incomplete state of activation. However, this phenotype is unique to the BB-DP rat, as deficiency in other intrinsic negative regulatory molecules alternatively leads to fulminant autoimmunity (TGF-β RII DN), expansion of the T cell compartment (Nfatc2 knockout) or no appreciable immune phenotype (Tob1 knockout). Tuning might engage molecules that control the transition from G0 to G1 and G1 progression, but there is a paucity of experiments to address the possible connection between these processes. We put this hypothesis to test using adoptive transfer of naive Tob1-knockout cells to MHC-deficient mice that were challenged 2 weeks later with Lewis Lung carcinoma cells. Unlike the results obtained using wild type naïve T cells, Tob1-knockout T cells did not prevent or delay tumor growth in the recipients, and the periphery showed a reverse phenotype with rapid erosion of CD4 T cells and protracted survival of CD8 T cells in peripheral lymphoid organs1
. This suggests that, much like absence of CD24 in DCs, the loss of intrinsic negative regulation created by knocking out the Tob1 gene shifted the balance of proliferation and death, allowing CD8 T cells to persist but leading to rapid erosion of CD4 T cells.
The dramatically different phenotypes observed upon adoptive transfer of wild type T cells and Tob1-knockout T cells into MHC-deficient mice indicates that MHC-dependent tuning and intrinsic negative regulation of T cell proliferation use non-redundant and cooperative signaling pathways, and that the consequences of losing one or both pathways are handled differently by naïve peripheral CD4 and CD8 T cells. A mechanistic explanation for these distinct phenotypes has not been elucidated, but co-stimulation is one attractive possibility (73
). In this scenario (), the survival of CD4 or CD8 T cells in an MHC-barren environment would be consistent with different thresholds for co-stimulation by CD28. Specifically, CD28 signaling is more robust in CD4 cells than in CD8 cells (105
) and can still be engaged by MHC-deficient dendritic cells (DC) that retain expression of CD80 and/or CD86 (108
An integrated model of T cell fates in an MHC-less environment
The importance of CD28 for optimal signal transduction has been recognized for some time (109
). CD28 is not necessary for T cell development in the thymus, and although CD28-deficient mice have reduced T cell help, they still mount effective cytolytic responses (e.g.
, against virus) (111
). During productive interactions between T cells and APCs, the binding of CD28 to CD80 (B7) or CD86 (B7.1) has various signaling consequences. First, this interaction (and those of other adhesion molecules) may stabilize the immunological synapse. Second, CD28 appears to link TCR signaling with the phosphoinositol-3 kinase (PI3K) pathways, either independently or cooperatively () (112
). Numerous roles have been characterized for PI3K signaling in T cells; phospholipid-inositol trisphosphate (PIP3
) with phosphorylated inositol at position-3 promotes activation of phospholipid-dependent kinase 1 (PDK1) and protein kinase-B/Akt, which in turn activate mitogen activated protein kinase (MAPK) pathways, protein kinase C-theta (PCKθ), cyclic AMP response element binding protein (CREB), and mammalian target of rapamycin (mTOR), while inhibiting Forkhead Box protein O (FoxO) and glycogen synthase kinase-3 (GSK-3) (112
). In addition to these signaling consequences, PI3K activation also promotes cell survival by modulating various Bcl-2 family members such as Bad (phosphorylation), Bcl-XL
(upregulation), and Bim (inhibition).
PI3K signaling also seems to impair Fas-dependent death signals. Specifically, T cells that express activated Akt fail to assemble caspase-8 to the death-inducing signaling complex (DISC) (116
). The lipid phosphorylation by PI3K is antagonized by the dual-specificity phosphatase PTEN (117
), a potent prototypical tumor suppressor protein. Among other defects, developmental PTEN-deficiency in mice results in lymphoma, and haploinsufficiency (loss of a single allele) leads to death by fulminant autoimmunity (118
). These PTEN-haploinsufficient mice show defective Fas-mediated apoptosis, and the phenotype of this defect resembles that of mice that carry an activated Akt allele (defective recruitment of caspase-8 to the DISC) (116
), establishing a link between PI3K activation and repression of both intrinsic (mitochondrial-dependent) and extrinsic (death factor-dependent) apoptosis. Nevertheless, various alternative mechanisms might explain the differential sensitivity of T cell subsets to self-MHC and the importance of intrinsic negative regulatory factors in sensitization and tuning. We predict that this will be a fertile area of investigation for some time to come.