IFN-αβ and Self-MHC Divert CD8 T Cells into a Distinct Differentiation Pathway Characterized by Rapid Acquisition of Effector Functions

Abstract

Non-virus-specific bystander CD8 T cells bathe in an inflammatory environment during viral infections. To determine if bystander CD8 T cells are affected by these environments, we examined P14, HY, and OT-I TCR transgenic CD8 T cells sensitized in vivo by IFN-αβ-inducing viral infections or by poly(I:C). These sensitized cells rapidly exerted effector functions such as IFN-γ production and degranulation on contact with their high affinity cognate antigen. Sensitization required self-MHC I and indirect effects of IFN-αβ, which together up-regulated the t-box transcription factor Eomesodermin, potentially enabling the T cells to rapidly transcribe CTL effector genes and behave like memory rather than naïve T cells. IL-12, IL-15, IL-18, and IFN-γ were not individually required for sensitization to produce IFN-γ, but IL-15 was required for up-regulation of granzyme B. These experiments indicate that naïve CD8 T cells receive signals from self-MHC and IFN-αβ and that by this process CD8 T cell responses to viral infection can undergo distinct differentiation pathways, depending on the timing of antigen encounter during the virus-induced IFN response.

Virus-Induced Transient Immune Suppression and the Inhibition of T Cell Proliferation by Type I Interferon

“…This sensitization was associated with a type I IFN-dependent upregulation of the transcription factor Eomes, which transcriptionally activates the IFN-␥ gene and other T cell effector genes, such as perforin. Of note is that the simple exposure of mice to the type I IFN-inducer poly(I ⅐ C) would upregulate Eomes in naïve T cells and sensitize them to rapidly become effector cells when encountering their cognate ligand (20). In the present study, we noted that the peak inhibition of bystander T cell proliferation occurred at day 3 after viral infection (Fig.…”

“…In a parallel study using similar transgenic and viral systems, we reported that naïve bystander CD8 T cells behaved like memory cells with regard to rapidly becoming activated to produce IFN-␥ upon encountering their cognate ligand (20). This sensitization was associated with a type I IFN-dependent upregulation of the transcription factor Eomes, which transcriptionally activates the IFN-␥ gene and other T cell effector genes, such as perforin.…”

“…This does not mean, however, that they are unchanged within the inflammatory milieu of an infection. Some naïve T cells will upregulate expression of CD69 and granzyme B, and we have recently reported that a subpopulation of those cells may respond to self-major histocompatibility complex (MHC) in the presence of type I IFN and upregulate expression of Eomesodermin (Eomes), a transcription factor important for T cell effector functions and memory (20). In this study, we sought to investigate whether bystander naïve CD8 T cells would be susceptible to immune suppression if the T cells were activated by cognate antigen during an acute viral infection in vivo.…”

Direct Effects of Type I Interferons on Cells of the Immune System

“…In many instances, T cells may sense IFN-I before the cognate antigen is actually presented to them. As a result of a preexposure to IFN-I, CD8 T cells become preactivated and acquire much faster effector functions upon antigen recognition (65). This preactivation may reflect the upregulation by IFN-I of several mRNAs in antigen-naive CD8 T lymphocyte, albeit without changes in the expression of the corresponding protein, unless antigen-specific activation ensues (64).…”

Human CD4+ effector T lymphocytes generated upon TCR engagement with self-peptides respond defectively to IL-7 in their transition to memory cells

“…Other studies have corroborated that in vivo TCR engagement with self-MHC in the presence of strong adjuvants (dsRNA, type I interferons (IFN)) led to bystander T-cell activation. 8,9 Thus, it is plausible that in these inflammatory settings, bystander lymphocytes might be activated by signals from mature DCs presenting self-Ag, as well as by the cytokine environment. Indeed, it has been demonstrated that the activation of human blood DCs, but not monocytes, is essential to initiate CD4…”