IL-12-Programmed Long-Term CD8+ T Cell Responses Require STAT4

Abstract

Immunological adjuvants activate innate immune cells for Ag presentation and elicitation of cytokines like IL-12 that promote T cell expansion and effector differentiation. An important but elusive aim for most immunization strategies is to produce memory T cells that provide durable immunity. Recent evidence demonstrates that the context of Ag presentation instructionally programs T cells for short- and long-term responses. However, the role and mechanisms by which cytokines like IL-12 condition CD8 T cells for long-term responses remain relatively uncharacterized. In this study, we show that brief exposure (20 h) of naive TCR-transgenic CD8 cells to IL-12 during Ag stimulation leads to transient phosphorylation of STAT4 for robust effector differentiation. Moreover, the IL-12-induced STAT4 engenders greater clonal expansion of the Ag-activated CD8 cells by regulating the expression of the transcriptional factor Bcl3- and Bcl2-related genes that promote survival of Ag-activated CD8 cells. Remarkably, the IL-12-conditioned CD8 T cells demonstrate increased sensitivity to IL-7 and IL-15, whereby they are rendered “fit” for homeostatic self-renewal as well as augmented CD4-dependent recall responses that are effective at controlling Salmonella infection in vivo. This information provides new insights into mechanisms by which IL-12 conditions CD8 T cells for long-term immunity, which is likely to benefit development of new strategies for the use of IL-12 in infectious diseases and cancer.

CD40 Is Required for Protective Immunity against Liver Stage Plasmodium Infection

“…CD40−/− CD8+ T cells primed in WT hosts also upregulated Itgam and Itgax less than WT CD8+ T cells, but intriguingly, CD40−/− CD8+ T cells upregulated Il12rb2 and Klrg1 even more than WT cells primed in WT hosts [Fig 6B, bottom]. Expression of the IL-12 receptor and IL-12 signaling have been associated with effector cell development but are also needed for survival and recall responses by CD8+ T cells (39, 40). Taken together, these data indicate that activation and differentiation of effector CD8+ T cells relied on CD40 expressed on the APC and not CD8+ T cell-autonomous CD40.…”

“…IL-12-deficient and IL-12 receptor-deficient cells do not survive well after immunization and they exhibit poor recall responses upon secondary stimulation (40, 67, 70). Increased expression of the Il12rb2 gene in CD4+ and CD8+ T cells in response to immunization with fabb/f- sporozoites could lead to increased cell survival and thus contribute to protective immunity.…”

TGF-β and IL-21 cooperatively stimulate activated CD8+ T cells to differentiate into Tc17 cells

“…Activated CD8 + cytotoxic T cells, such as CD4 + helper T cells, acquire cytokine-producing phenotypes orchestrated by lineage-specific transcription factors. For example, IL-12 enhances differentiation into IFN-␥-producing Tc1 cells and expression of the transcription factors T-bet and eomesodermin [1][2][3]. The development of IL-17-producing Tc17 cells is promoted by TGF-␤ together with IL-6 or IL-21 [4,5].…”

SOCS1 downregulation in dendritic cells promotes memory T-cell responses

“…IL-15 is crucial for antigen-specific CD8 + T cell proliferation [5,7,8]. IL-12 conditions CD8 + T cells for long-term immunity by increasing sensitivity to IL-7 and IL-15 [9]. These and other cytokines work together to generate and maintain memory CD4 + and CD8 + T cells.…”