A Critical Role of IL-21-Induced BATF in Sustaining CD8-T-Cell-Mediated Chronic Viral Control

Abstract

Summary Control of chronic viral infections by CD8 T cells is critically dependent on CD4 help. In particular, helper-derived IL-21 plays a key role in sustaining the CD8 T cell response, however the molecular pathways by which IL-21 sustains CD8 T cell immunity remain unclear. We demonstrate that IL-21 causes a phenotypic switch of transcription factor expression in CD8 T cells during chronic viral infection characterized by sustained BATF expression. Importantly, BATF expression during chronic infection is both required for optimal CD8 T cell persistence and anti-viral effector function, and sufficient to rescue “unhelped” CD8 T cells. Mechanistically, BATF sustains the response by cooperating with IRF4, an antigen-induced transcription factor that is also critically required for CD8 T cell maintenance, to preserve Blimp-1 expression and thereby sustain CD8 T cell effector function. Collectively, these data suggest that CD4 T cells “help” the CD8 response during chronic infection via IL-21-induced BATF expression.

Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells

“…Our findings revealed that BATF transcript is upregulated in tumor-infiltrating Treg cells more than in tumor infiltrating Th17 cells (Figure S4). Expression of BATF in CD8 + T cells is induced by IL-21 (Xin et al., 2015), and we found that IL21R is highly expressed in tumor-infiltrating Treg cells (Figure 4). …”

Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer

“…For example, several promising molecules that we identified, such as CD38, CD39, BATF, NAB1, KIR2DL4, SIPRG and components of Notch signaling, deserve further investigation as immunotherapeutic targets in cancer. BATF has been shown to regulate the metabolism and survival of CD8 + T cells and to diminish the inhibited phenotype of CD8 + T cells 48,49 . In a model of infection with lymphocytic choriomeningitis virus, the expression of BATF in CD8 + T cells, induced by the cytokine IL-21 derived from CD4 + T cells, was shown to be essential for maintaining the effector response of CTLs, and overexpression of BATF restored the effector function of CD8 + T cells that had not received help from CD4 + T cells 49 .…”

“…BATF has been shown to regulate the metabolism and survival of CD8 + T cells and to diminish the inhibited phenotype of CD8 + T cells 48,49 . In a model of infection with lymphocytic choriomeningitis virus, the expression of BATF in CD8 + T cells, induced by the cytokine IL-21 derived from CD4 + T cells, was shown to be essential for maintaining the effector response of CTLs, and overexpression of BATF restored the effector function of CD8 + T cells that had not received help from CD4 + T cells 49 . NAB1 is a transcription factor whose mouse homolog (NAB2) is induced in CD8 + T cells that have received help from CD4 + T cells and is needed to prevent activation-induced cell death of those ‘helped’ CD8 + T cells 50 .…”

IL-21 and T Cell Differentiation: Consider the Context

“…revealed that IL-21 maintains functional CD8 T cells during chronic LCMV infection by sustaining the expression of the transcription factor basic leucine transcription factor, ATF-like (BATF) via the activation of STAT3 [76]. In vitro studies further indicate that IL-21-induced BATF cooperates with IRF4 to induce the expression of the transcriptional regulator B lymphocyte-induced maturation protein 1 (Blimp1) [76], which can both enhance the effector functions of CD8 T cells [77–79], as well as exacerbate exhaustion and the expression of inhibitory receptors [78]. Indeed, BATF-deficient virus-specific CD8 T cells express lower levels of the inhibitory receptors PD-1 and 2B4 [76].…”

“…In vitro studies further indicate that IL-21-induced BATF cooperates with IRF4 to induce the expression of the transcriptional regulator B lymphocyte-induced maturation protein 1 (Blimp1) [76], which can both enhance the effector functions of CD8 T cells [77–79], as well as exacerbate exhaustion and the expression of inhibitory receptors [78]. Indeed, BATF-deficient virus-specific CD8 T cells express lower levels of the inhibitory receptors PD-1 and 2B4 [76]. Therefore, it will be important to pinpoint how the IL-21-STAT3-BATF axis controls the levels of Blimp1 and how its regulatory activities are influenced by the degree of antigenic stimulation and presence of other activating or inhibitory signals.…”