Surprisingly, however, selective activation of ERK similarly leads to rapid expansion of LCMV-specific T cells without causing cell death, and results instead in T cells with a memory phenotype.
We find that enhanced DAG signaling leads to rapid expansion of LCMV-specific T cells, which is followed by enhanced Bim expression and complete collapse of this T cell pool at later stages of infection. Here, we tested how DAG signaling affects T cell responses during chronic infection with LCMV CL13.
Conversely, CD8 + T cells deficient in DGKζ display increased ERK activation and heightened cytotoxicity and cytokine production, leading to enhanced responsiveness towards cancer ( 18) and acute viral infection ( 16, 19). For example, overexpression of DGKζ inhibits TCR signaling by reducing the levels of active GTP-bound Ras and, consequently, diminishing ERK activation ( 17). Although DGKζ-deficient mice harbor normal numbers of thymocytes and splenocytes ( 16), DGKζ does affect T cell function. DGKζ, one of the isoforms of DGK, serves as a critical negative regulator of DAG signaling and can modulate the strength of TCR signaling ( 15). DAG is essential for the activation of diverse downstream signaling cascades including the Ras-extracellular signal-related kinase (ERK)-activator protein (AP)-1 pathway, the protein kinase C (PKC)θ-IκB kinase (IKK)-nuclear factor (NF)-κB pathway, and the AK strain transforming (AKT)-tuberous sclerosis complex (TSC)1/2-mammalian target of rapamycin (mTOR) pathway ( 11, 12).ĭAG signaling is negatively regulated by diacylglycerol kinases (DGK), which phosphorylate DAG, converting it into phosphatidic acid (PA) ( 12– 14). PLCγ1 is an enzyme that hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP 2) to generate two second messengers, inositol 1,4,5-trisphosphate (IP 3) and diacylglycerol (DAG). One of the most important proximal signaling events that occurs downstream of TCR engagement is the activation of phospholipase Cγ1 (PLCγ1). During the first week of viral infection, virus-specific T cells expand in secondary lymphoid organs through stimulation of their T cell receptor (TCR) by viral antigens presented by antigen presenting cells. The LCMV CL13-induced prolonged antigen persistence and inflammatory environment induced by LCMV CL13 elicits T cell exhaustion.Īlthough many of the receptors involved and the events that participate in the induction of T cell exhaustion are well-studied, how early T cell activation affects the outcome of T cell responses in chronic viral infection are less well understood.
In contrast to the parental acute strain (LCMV Armstrong), the lysine to glutamine L1079 mutation in LCMV Clone 13 (LCMV CL13) isolate allows it to replicate more rapidly, increasing the levels of antigen, and inducing higher and longer lasting viremia ( 9, 10). LCMV infection has become a staple system for testing and discovering fundamental immunological concepts since its use in the 1930s ( 9), and the ability of an LCMV variant to establish chronic infection was critical for the discovery of T cell exhaustion. Subsequently, CD8 + T cell exhaustion was demonstrated in other animal models and in humans with chronic viral (HIV, HBV, HCV), bacterial, and parasitic infections as well as in cancer ( 6). CD8 + T cell exhaustion was initially reported more than two decades ago in mice infected with a chronic form of lymphocytic choriomeningitis virus (LCMV) ( 3, 4). Exhausted CD8 + T cells express an altered transcriptional program that leads to a loss of robust effector function and to the persistent expression of multiple inhibitory receptors ( 2). This continuous exposure induces the dampening of T cell function, termed T cell exhaustion ( 1– 8).
CD8 + T cells are exposed to persistent antigen and inflammatory signals during chronic infections and cancer. CD8 + T cells are important in defense against viral infections and cancer.
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