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Abstract
The TNFR family member OX40 (CD134) is critical for optimal clonal expansion and survival of T cells. However, the intracellular targets of OX40 in CD8 T cells are not fully understood. Here we show that A1, a Bcl-2 family protein, is regulated by OX40 in effector CD8 T cells. In contrast to wild-type T cells, OX40-deficient CD8 T cells failed to maintain A1 expression driven by antigen. Conversely, enforced OX40 stimulation promoted A1 expression. In both situations, the expression of A1 directly correlated with CD8 T cell survival. In addition, exogenous expression of A1 in OX40-deficient CD8 T cells reversed their survival defect in vitro and in vivo. Moreover, forced expression of A1 in CD8 T cells from OX40-deficient mice restored the ability of these T cells to suppress tumor growth in a murine model. These results indicate that OX40 signals regulate CD8 T cell survival at least in part through maintaining expression of the anti-apoptotic molecule A1, and provide new insight into the mechanism by which OX40 may impact anti-tumor immunity.
Highlights
Costimulatory signals perform an important function in modulating adaptive and regulatory immunity
In mouse studies of infectious disease, antigen specific CD8 T cell responses were compromised in the absence of OX40 after infection with influenza virus, cytomegalovirus, vaccinia virus, Listeria monocytogenes (Lm), or lymphocytic choriomeningitis virus (LCMV) [7,8,9,10,11]
OX40 KO CD8 T cells are sensitive to apoptosis and defective in their ability to proliferate during the initial primary response [2]
Summary
Costimulatory signals perform an important function in modulating adaptive and regulatory immunity. In mouse studies of infectious disease, antigen specific CD8 T cell responses were compromised in the absence of OX40 after infection with influenza virus, cytomegalovirus, vaccinia virus, Listeria monocytogenes (Lm), or lymphocytic choriomeningitis virus (LCMV) [7,8,9,10,11]. Systemic injection of an agonist antibody to OX40 has strongly enhanced the development of effector or memory CD8 T cells in basic systems [12], after virus infection [13,14], and in models of tumor immunity [3,15,16,17,18,19]. The intracellular targets of OX40 that regulate CD8 T cells have not been defined
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