CD8 T Cells in Innate Immune Responses: Using STAT4-Dependent but Antigen-Independent Pathways to Gamma Interferon during Viral Infection

Abstract

The cytokine gamma interferon (IFN-γ), with antimicrobial and immunoregulatory functions, can be produced by T cells following stimulation through their T cell receptors (TCRs) for antigen. The innate cytokines type 1 IFNs and interleukin-12 (IL-12) can also stimulate IFN-γ production by natural killer (NK) but not naive T cells. High basal expression of signal transducer and activator of transcription 4 (STAT4), used by type 1 IFN and IL-12 to induce IFN-γ as well as CD25, contributes to the NK cell responses. During acute viral infections, antigen-specific CD8 T cells are stimulated to express elevated STAT4 and respond to the innate factors with IFN-γ production. Little is known about the requirements for cytokine compared to TCR stimulation. Primary infections of mice with lymphocytic choriomeningitis virus (LCMV) demonstrated that although the elicited antigen-specific CD8 T cells acquired STAT4-dependent innate cytokine responsiveness for IFN-γ and CD25 induction ex vivo, TCR stimulation induced these through STAT4-independent pathways. During secondary infections, LCMV-immune CD8 T cells had STAT4-dependent IFN-γ expression at times of innate cytokine induction but subsequently expanded through STAT4-independent pathways. At times of innate cytokine responses during infection with the antigen-distinct murine cytomegalovirus virus (MCMV), NK and LCMV-immune CD8 T cells both had activation of pSTAT4 and IFN-γ. The T cell IFN-γ response was STAT4 and IL-12 dependent, but antigen-dependent expansion was absent. By dissecting requirements for STAT4 and antigen, this work provides novel insights into the endogenous regulation of cytokine and proliferative responses and demonstrates conditioning of innate immunity by experience.

Cytokine-Mediated Activation of NK Cells during Viral Infection

“…Eight days after LCMV infection, NK cell-mediated IFN-␥ responses to inflammatory cytokines were reduced, and this is in contrast to LCMV-specific CD8 ϩ T cells that were highly responsive to cytokine stimulation at this time point (30). Similar to observations of virus-specific CD8 ϩ T cells (30,46,47), several cytokine combinations induced CD69 and/or CD25 upregulation in a majority of NK cells (e.g., IL-18 plus IFN-␤) but only triggered IFN-␥ production in a more limited subset of the NK cells. These differences were more pronounced in NK cells from BALB/c mice ( Fig.…”

Dissecting CD8+ NKT Cell Responses to Listeria Infection Reveals a Component of Innate Resistance

“…The notion that T cells can perform as innate cells has been previously proposed and debated in a number of reports (6, 7, 14, 15, 37–39). While the role of NK cells producing IFNγ during the early phase of Listeria infection is indisputable, Anderson et al showed evidence of early IFNγ production in the absence of NK cells (37).…”

“…Ruiz et al identified this population of memory CD8 + T cells as NK1.1 + CD8 + T cells (13). Similarly lymphocytic choriomeningitis virus (LCMV)-primed memory CD8 + T cells were able to rapidly produce innate IFNγ upon infection with murine cytomegalovirus (MCMV) infection in an antigen-independent manner (15). However, these innate capabilities were identified in the context of prior pathogen exposure.…”

Cytoplasmic STAT4 Promotes Antiviral Type I IFN Production by Blocking CHIP-Mediated Degradation of RIG-I

“…STAT6 has also been proved to promote the antiviral response of innate cells by inducing specific target genes responsible for immune cell homing (21). STAT4, which mediates IL-12-induced signaling pathway, has been reported to limit kinds of viral infection in host, such as lymphocytic choriomeningitis virus (22,23), murine CMV virus (24), and HSV-2 (25). Moreover STAT4-dependent IFN-g production is protective for host during virus infection (22)(23)(24)(25).…”

“…STAT4, which mediates IL-12-induced signaling pathway, has been reported to limit kinds of viral infection in host, such as lymphocytic choriomeningitis virus (22,23), murine CMV virus (24), and HSV-2 (25). Moreover STAT4-dependent IFN-g production is protective for host during virus infection (22)(23)(24)(25). However, the role of STAT4 in regulating the innate sensing of invading pathogens and subsequent activation of innate signaling for initiating antiviral innate immune response remains unclear.…”