The Transcription Factor NFAT Promotes Exhaustion of Activated CD8 + T Cells

An IRF8-dependent subset of conventional dendritic cells (cDCs), termed cDC1, effectively cross-primes CD8+ T cells and facilitates tumor-specific T cell responses. Etv6 is an ETS family transcription factor that controls hematopoietic stem and progenitor cell (HSPC) function and thrombopoiesis. We report that like HSPCs, cDCs express Etv6, but not its antagonist, ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow impaired the generation of cDC1-like cells in vitro and abolished the expression of signature marker CD8α on cDC1 in vivo. Moreover, Etv6-deficient primary cDC1 showed a partial reduction of cDC-specific and cDC1-specific gene expression and chromatin signatures and an aberrant up-regulation of pDC-specific signatures. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and the generation of tumor antigen–specific CD8+ T cells. Thus, Etv6 optimizes the resolution of cDC1 and pDC expression programs and the functional fitness of cDC1, thereby facilitating T cell cross-priming and tumor-specific responses.

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Cutting Edge: Transcription Factor BCL6 Is Required for the Generation, but Not Maintenance, of Memory CD8+ T Cells in Acute Viral Infection

The Journal of Immunology ◽

10.4049/jimmunol.1900014 ◽

2019 ◽

Vol 203 (2) ◽

pp. 323-327 ◽

Cited By ~ 5

Author(s):

Zhenyu Liu ◽

Yanyan Guo ◽

Shupei Tang ◽

Lan Zhou ◽

Chunji Huang ◽

...

Keyword(s):

T Cells ◽

Transcription Factor ◽

Viral Infection ◽

Cd8 T Cells ◽

Cutting Edge ◽

Memory Cd8 T Cells ◽

Acute Viral Infection

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Is the Antiproteinuric Effect of Cyclosporine A Independent of Its Immunosuppressive Function in T Cells?

International Journal of Nephrology ◽

10.1155/2012/809456 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6

Author(s):

Bin Zhang ◽

Wei Shi

Keyword(s):

T Cells ◽

Transcription Factor ◽

Cyclosporine A ◽

Immunosuppressive Effect ◽

Molecular Event ◽

Podocyte Injury ◽

Antiproteinuric Effect ◽

Nfat Activation ◽

Per Se ◽

Transcription Factor Nfat

The antiproteinuric effect of cyclosporine A(CsA) has been believed to result from its immunosuppressive effect on the transcription factor NFAT in T cells. However, current evidences supporting this hypothesis are missing. A recent study showed that CsA has a direct antiproteinuric effect on podocytes, suggesting a novel non-immunosuppressive mechanism for CsA's antiproteinuric effect. Conditional NFATc1 activation in podoyctes per se is sufficient to induce proteinuria in mice, indicating that NFAT activation in podocytes is a critical pathogenic molecular event leading to podocyte injury and proteinuria. Meanwhile, evidence showed that TRPC6-mediated Ca2+influx stimulates NFAT-dependent TRPC6 expression. Altogether, these advances in podocyte research indicate that calcineurin-NFAT signal or calcineurin-synaptopodin axis has a direct proteinuric effect on podocytes which raises the possibility of developing specific antiproteinuric drugs that lack the unwanted effects of calcineurin or NFAT inhibition.

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Exploring the Biological Role of Kruppel-Like Factor 2 In Cytotoxic T Lymphocytes

Blood ◽

10.1182/blood.v116.21.2783.2783 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2783-2783

Author(s):

Gavin Charles Preston ◽

Doreen A Cantrell

Keyword(s):

T Cells ◽

Transcription Factor ◽

T Cell ◽

Cell Survival ◽

Cytotoxic T Lymphocytes ◽

Adhesion Molecule ◽

Cd8 T Cells ◽

T Cell Memory ◽

Transcriptional Program ◽

T Cell Survival

Abstract Abstract 2783 Kruppel-like factor 2 (KLF2) is a transcription factor which has been shown to be a critical regulator of T lymphocyte quiescence and trafficking. KLF2 is highly expressed in naïve CD8 T cells but its expression is transcriptionally downregulated in effector cytotoxic T lymphocytes (CTL). To understand how KLF2 might co-ordinate biological processes in CTL, we have determined the impact of preventing KLF2 downregulation on the transcriptional program of antigen receptor triggered CD8 T cells. Our data show that CTL which fail to downregulate KLF2 have a strikingly different transcriptional program to normal CTL. Immune activated CD8 T cells that sustain KLF2 expression thus show increased expression of 672 genes and decreased expression of 205 genes compared to normal CTL that have lost KLF2. Previous studies have indicated that high levels of KLF2 correlate with long term T cell survival and the development of memory CD8 T cells. We therefore questioned whether the KLF2 regulated genes identified in our experiments gave any insight as to why increasing levels of KLF2 in immune activated T cells might control T cell memory. In this context, we noted that KLF2 downregulation is necessary for TCR triggering of the CTL mitotic pathway. The molecular basis for this effect includes that KLF2 drives expression of intracellular cell cycle inhibitors. It was equally striking, however, that KLF2 could induce expression of the inhibitory receptor Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (Ceacam1, CD66a), which can suppress the T cell proliferative response. The present report confirms that KLF2 controls the repertoire of chemokine receptors and adhesion molecules expressed by CTL. Previous studies have identified the adhesion molecule CD62L and the G protein coupled receptor S1P1 as direct gene targets for KLF2. The present data support that KLF2 positively regulates expression of these molecules but also describes a cell autonomous role for KLF2 to negatively regulate the expression of the inflammatory chemokine receptor CXCR3 in antigen primed CTL. The loss of KLF2 is thus essential to allow CTL to traffic to CXCR3 ligands. One other striking observation was that KLF2 expression in CTL upregulates expression of the IL-6 receptor and Serine Protease Inhibitor 6 (Spi6). The latter molecule has a key role in protecting CTL from self injury inflicted by granzymes and is critical for the generation of T cell memory. IL-6 receptor expression is similarly important for memory T cell survival. Collectively, these data identify new KLF2 regulated genes and biological functions in CD8 T cells and provide important insights as to how this transcription factor controls T cell immune responses and might determine the effector/memory fate of a CTL. Disclosures: No relevant conflicts of interest to declare.

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