CD8 T Cell Clonal Expansion and Development of Effector Function Require Prolonged Exposure to Antigen, Costimulation, and Signal 3 Cytokine

It has been reported that MHC class I-restricted Ag presentation persists for only a short period following infection with certain pathogens, declining in parallel with the emergence of specific CTL activity. We have examined this issue in the case of murine infection with HSV-1. We found that the period of Ag presentation capable of priming naive CD8+ T cells is comparatively prolonged, persisting for at least 7 days after infection, and continuing despite the appearance of localized CTL activity. Ag presentation was abbreviated to 3 or 4 days postinfection by surgical excision of the inoculation site early after infection. This intervention attenuated the size of the primary CTL response, implying that prolonged presentation is necessary to drive maximal CTL expansion. Combined, these data show that, in some types of infection, CTL priming can extend well beyond the first 24–48 h after primary inoculation.

Section: Discussionmentioning

confidence: 99%

Cutting Edge: Prolonged Antigen Presentation after Herpes Simplex Virus-1 Skin Infection

Stock

Mueller

Lint

et al. 2004

“…IL-12 needs to be present from ϳ15-60 h after stimulation with Ag/B7 for maximal response and development of effector function by 72 h, the peak of cytolytic activity (18), and we therefore examined mRNA expression at 24, 48, and 72 h (Fig. 3.) Expression of mRNA for granzyme B (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cutting Edge: Type I IFNs Provide a Third Signal to CD8 T Cells to Stimulate Clonal Expansion and Differentiation

Curtsinger

Valenzuela

Agarwal

et al. 2005

Self Cite

540

492

In this study, we show that IFN-αβ can have a direct role in linking innate and adaptive responses by providing the “third signal” needed by naive CD8 T cells responding to Ag and costimulatory ligands. Stimulation of CD8 T cells in the absence of a third signal leads to proliferation, but clonal expansion is limited by poor survival and effector functions do not develop. We show that IFN-αβ can provide the third signal directly to CD8 T cells via a STAT4-dependent pathway to stimulate survival, development of cytolytic function, and production of IFN-γ. Provision of the third signal by either IFN-αβ or IL-12 results in regulation of the expression of a number of genes, including several that encode proteins critical for effector function.

“…Inflammatory cytokines produced early during infection are believed to play an important role in the differentiation of naive T cells into IFN-␥-producing effector cells. Two wellcharacterized inflammatory cytokines that can influence the differentiation of T cells are IL-12 and type I IFN (IFN-I) (1)(2)(3)(4)(5). Most of the studies examining the signals required for T cell activation and priming for IFN-␥ production were conducted in vitro by stimulating T cells with plastic beads coated with MHC ligands plus peptide in the presence of exogenously added cytokines (1)(2)(3).…”

Section: Nterferon-␥ Plays An Important Protective Role In Both Innatementioning

confidence: 99%

IL-12 and Type-I IFN Synergize for IFN-γ Production by CD4 T Cells, Whereas Neither Are Required for IFN-γ Production by CD8 T Cells afterListeria monocytogenesInfection

Way

Havenar-Daughton

Kolumam

et al. 2007

Differentiation of Ag-specific T cells into IFN-γ producers is essential for protective immunity to intracellular pathogens. In addition to stimulation through the TCR and costimulatory molecules, IFN-γ production is thought to require other inflammatory cytokines. Two such inflammatory cytokines are IL-12 and type I IFN (IFN-I); both can play a role in priming naive T cells to produce IFN-γ in vitro. However, their role in priming Ag-specific T cells for IFN-γ production during experimental infection in vivo is less clear. In this study, we examine the requirements for IL-12 and IFN-I, either individually or in combination, for priming Ag-specific T cell IFN-γ production after Listeria monocytogenes (Lm) infection. Surprisingly, neither individual nor combined defects in IL-12 or IFN-I signaling altered IFN-γ production by Ag-specific CD8 T cells after Lm infection. In contrast, individual defects in either IL-12 or IFN-I signaling conferred partial (∼50%) reductions, whereas combined deficiency in both IL-12 and IFN-I signaling conferred more dramatic (75–95%) reductions in IFN-γ production by Ag-specific CD4 T cells. The additive effects of IL-12 and IFN-I signaling on IFN-γ production by CD4 T cells were further demonstrated by adoptive transfer of transgenic IFN-IR+/+ and IFN-IR−/− CD4 T cells into normal and IL-12-deficient mice, and infection with rLm. These results demonstrate an important dichotomy between the signals required for priming IFN-γ production by CD4 and CD8 T cells in response to bacterial infection.