Abstract
PI3Ks regulate diverse immune cell functions by transmitting intracellular signals from Ag, costimulatory receptors, and cytokine receptors to control cell division, differentiation, survival, and migration. In this study, we report the effect of inhibiting the p110δ subunit of PI3Kδ on CD8+ T cell responses to infection with the intracellular bacteria Listeria monocytogenes. A strong dependency on PI3Kδ for IFN-γ production by CD8+ T cells in vitro was not recapitulated after Listeria infection in vivo. Inactivation of PI3Kδ resulted in enhanced bacterial elimination by the innate immune system. However, the magnitudes of the primary and secondary CD8+ T cell responses were reduced. Moreover, PI3Kδ activity was required for CD8+ T cells to provide help to other responding CD8+ cells. These findings identify PI3Kδ as a key regulator of CD8+ T cell responses that integrates extrinsic cues, including those from other responding cells, to determine the collective behavior of CD8+ T cell populations responding to infection.
Highlights
Phosphorylation of Akt, Foxo transcription factor (TF), and p70S6K was profoundly diminished in p110dD910A CD8+ T cells (Fig. 1A), indicating that p110d is the predominant PI3K isoform contributing to Akt phosphorylation in CD8+ T cells
We found that PI3Kd inactivation reduced yellow fluorescent protein (YFP) and IFN-g expression in CD8+ T cells (Fig. 1B)
We have shown that PI3Kd controls the magnitude of both primary and secondary CD8+ T cell responses in response to infection with the intracellular bacterial pathogen L. monocytogenes
Summary
We show that the magnitude of both primary and secondary CD8+ T cell responses to L. monocytogenes infection is reduced in p110dD910A mice. In p110dD910A mice the numbers of Tet+CD8+ T cells were reduced at the peak of the primary response (8 d postinfection) in all organs examined (Fig. 2C).
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