Pretreatment of activated human CD8 T cells with IL-12 leads to enhanced TCR-induced signaling and cytokine production

Abstract

During the immune response to pathogens and autoantigens, CD8 T cells are exposed to numerous inflammatory agents including the cytokine IL-12. Previous studies have focused on how IL-12 regulates T cell functions when present during or after the activation of the T cell receptor (TCR). However, recent studies suggest that prior exposure to IL-12 also alters the TCR responsiveness of murine T cells. Whether similar phenomena occur in human activated CD8 T cells and the mechanisms mediating these effects remain unexplored. In this study, we observed that pretreatment of human activated CD8 T cells with IL-12 results in increased cytokine mRNA and protein production following subsequent TCR challenge. The potentiation of TCR-mediated cytokine release was transient and required low doses of IL-12 for at least 24 hours. Mechanistically, prior exposure to IL-12 increased the TCR induced activation of select MAPKs and AKT without altering the activation of more proximal TCR signaling molecules, suggesting that the IL-12 mediated changes in TCR signaling are responsible for the increased production of cytokines. Our data suggest that prior treatment with IL-12 potentiates human CD8 T cell responses at sites of infection and inflammation, expanding our understanding of the function of this clinically important cytokine.

Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations

“…When we analyzed all of our data for correlations, we found significant correlations between plasma cytokine abundance and measures of T cell metabolism, which were unique in patients with ME/CFS compared with controls. ME/CFS CD8 + T cell glycolysis had multiple significant correlations with cytokines that are known to be proinflammatory or with growth factors (63)(64)(65). This is especially interesting, given the reduced basal glycolysis we observed in patients with ME/CFS.…”

Immunology of IL-12: An update on functional activities and implications for disease

“…Interestingly, STAT4 is required for the production of IFN-γ downstream of IL-12 in both CD4 + and CD8 + T cells, but only CD4 + T cells require IL-12 and STAT4 for the production of IFN-γ following antigen recognition and T cell receptor (TCR) signaling suggesting alternative regulatory pathways in different lymphocyte subsets (Trinchieri, 2003[ 184 ]; Carter and Murphy, 1999[ 30 ]). It was also shown that IL-12 pre-treatment of CD4 + and CD8 + T cells enhances TCR-induced IFN-γ, tumor necrosis factor alpha (TNF-α), IL-13, IL-4 and IL-10 production and intensifies oxidative metabolism (Vacaflores et al, 2016[ 191 ], 2017[ 192 ]).…”

Befriending the Hostile Tumor Microenvironment in CAR T-Cell Therapy

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