T-bet is required for optimal production of IFN-γ and antigen-specific T cell activation by dendritic cells

Lugo-Villarino, Geanncarlo; Maldonado-López, Roberto; Possemato, Richard; Peñaranda, Cristina; Glimcher, Laurie H.

doi:10.1073/pnas.1332767100

Cited by 236 publications

(222 citation statements)

References 51 publications

Supporting

Mentioning

209

Contrasting

Unclassified

Order By: Relevance

“…T-bet has been identified as a master regulatory gene responsible for Th1 T cell differentiation and for IFN-c production in NK cells, CD4 + and CD8 + T cells, B cells, and dendritic cells [3,[5][6][7][8][9]. Given its critical role, it is not surprising that abnormal T-bet expression can be associated with diseases characterized by imbalance between Th1-Th2 or aberrant IFN-c gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…T-bet has also recently been shown to regulate murine IFN-c production by B effector 1 cells [8]. In addition, T-bet is required by dendritic cells for the optimal production of IFN-c and for full activation of antigen-specific Th1 cells [9]. Experiments in T-bet -/-mice support its importance in control of Leishmania major infection, lymphocytic choriomeningitis virus infection, insulin dependent diabetes, inflammatory bowel disease, experimental allergic encephalomyelitis, asthma and other Th1-mediated diseases [3,[10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Transcriptional control of human T‐BET expression: The role of Sp1

Min

Boyd

et al. 2007

Eur J Immunol

View full text Add to dashboard Cite

Murine T-bet (T-box expressed in T cells) is a master regulator of IFN-c gene expressionin NK and T cells. T-bet also plays a critical role in autoimmunity, asthma and other diseases. However, cis elements or trans factors responsible for regulating T-bet expression remain largely unknown. Here, we report on our discovery of six Sp1-binding sites within the proximal human T-BET promoter that are highly conserved among mammalian species. Electrophoretic mobility shift assays demonstrate a physical association between Sp1 and the proximal T-BET promoter with a direct dose response between Sp1 expression and T-BET promoter activity. Ectopic overexpression of Sp1 also enhanced T-BET expression and cytokine-induced IFN-c secretion in NK cells and T cells. Mithramycin A, which blocks the binding of Sp1 to the T-BET promoter, diminished both T-BET expression and IFN-c protein production in monokine-stimulated primary human NK cells. Collectively, our results suggest that Sp1 is a positive transcriptional regulator of T-BET. As T-BET and IFN-c are critically important in inflammation, infection, and cancer, targeting Sp1, possibly with mithramycin A, may be useful for preventing and/ or treating diseases associated with aberrant T-BET or IFN-c expression.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcriptional control of human T‐BET expression: The role of Sp1

Min

Boyd

et al. 2007

Eur J Immunol

View full text Add to dashboard Cite

show abstract

“…T-bet expression regulates the production of IFN-␥ in CD4 T cells (16), CD8 T cells (19), ␥␦ T cells (18), dendritic cells (20), and NK cells (21). Furthermore, T-bet also regulates the development of cytotoxic effector responses (33) and isotype switching in B cells (34).…”

Section: T-bet Deficiency In Non-cd4 T Cells Does Not Affect Salmonelmentioning

confidence: 99%

“…Therefore, T-bet expression by cells other than CD4 T cells could influence the generation of IFN-␥-producing CD4 T cells and affect protective immunity to Salmonella infection. Of particular interest is the observation that T-bet regulated IFN-␥ production by dendritic cells can contribute to the development of Th1 responses in vivo (20). We therefore examined the development of Wt Salmonella-specific Th1 cells that had been activated in a T-bet-deficient environment.…”

Section: T-bet Deficiency In Non-cd4 T Cells Does Not Affect Salmonelmentioning

confidence: 99%

Expression of T-bet by CD4 T Cells Is Essential for Resistance toSalmonellaInfection

Ravindran

Foley

Stoklasek

et al. 2005

The Journal of Immunology

Self Cite

137

145

View full text Add to dashboard Cite

Despite the recognized role of the T-bet transcription factor in the differentiation of Th1 cells, T-bet-deficient mice can develop small numbers of IFN-γ-producing CD4 T cells. Although these are not sufficient to allow normal handling of some pathogens, T-bet-deficient mice do resolve infection with the intracellular pathogen Listeria monocytogenes. In contrast, we report that expression of T-bet is required for resistance to Salmonella infection. T-bet-deficient mice succumbed to infection with attenuated Salmonella and did not generate IFN-γ-producing CD4 T cells or isotype-switched Salmonella-specific Ab responses. Spleen cells from Salmonella-infected T-bet-deficient mice secreted increased levels of IL-10, but not IL-4, upon in vitro restimulation. A Salmonella-specific TCR transgenic adoptive transfer system was used to further define the involvement of T-bet expression in the development of Salmonella-specific Th1 cells. Wild-type Salmonella-specific CD4 T cells activated in T-bet-deficient recipient mice displayed no defect in clonal expansion, contraction, or IFN-γ production. In contrast, T-bet-deficient, Salmonella-specific CD4 T cells activated in wild-type recipient mice produced less IFN-γ and more IL-2 upon in vivo restimulation. Therefore, expression of T-bet by CD4 T cells is required for the development of Salmonella-specific Th1 cells, regulation of IL-10 production, and resistance to Salmonella infection.

show abstract

“…12 In the last few years, it has been reported that one of the major effects of IL-12 on these cells is the induction of interferon-c (IFN-c) production, 13 which involves Stat4 and T-bet transcriptional factors. 14,15 Because of this effect of IL-12, some of its autocrine activities on DCs seem to be mediated by endogenous IFN-c. 3 The direct effect of IL-23 on IFN-c production by DCs has not yet been evaluated, but IL-23 induces IL-12 secretion by DCs, 12 which might contribute to IFN-c production by these cells. Moreover, the referred study also shows that IL-23 promotes peptide presentation equally well for both CD8 -and CD8 + DC subsets, whereas IL-12 acts selectively on CD8 -DCs.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

Analysis of the activation profile of dendritic cells derived from the bone marrow of interleukin‐12/interleukin‐23‐deficient mice

et al. 2005

View full text Add to dashboard Cite

SummaryWe have previously shown that macrophages from interleukin (IL)-12p40 gene knockout (IL-12/IL-23 -/-) mice have a bias towards the M2 activation profile, spontaneously secreting large quantities of transforming growth factor-b1 (TGF-b1) and producing low levels of nitric oxide (NO) in response to lipopolysaccharide (LPS) and interferon-c (IFN-c). To verify whether the activation profile of dendritic cells (DCs) is also influenced by the absence of IL-12/IL-23, bone marrow-derived DCs from IL-12/IL-23 -/-and C57BL/6 mice were evaluated. At first we noticed that % 50% of the C57BL/6 DCs were dead after LPS-induced maturation, whereas the mortality of IL-12/IL-23 -/-DCs was < 10%, a protective effect that diminished when recombinant IL-12 (rIL-12) was added during maturation. Similarly to macrophages, mature IL-12/IL-23 -/-DCs (mDCs) produced higher levels of TGF-b1 and lower levels of NO than C57BL/6 mDCs. NO release was IFN-c-dependent, as evidenced by the poor response of IFN-c -/-and IL-12/IL-23 -/-IFN-c -/-mDCs. Nevertheless, IFN-c deficiency was not the sole reason for the weak NO response observed in the absence of IL-12/IL-23. The high level of TGF-b1 secretion by IL-12/IL-23 -/-mDCs could explain why exogenous IFN-c partially restored the NO production of IFN-c -/-mDCs, while IL-12/IL-23 -/-IFN-c -/-mDCs remained unresponsive. We also showed that CD4 + T-cell proliferation was inhibited by C57BL/6 mDCs, but not by IL-12/IL-23 -/-mDCs. IFN-c and NO appear to mediate this antiproliferative effect because this effect was not observed in the presence of mDCs from IFN-c -/-or IL-12/IL-23 -/-IFN-c -/-mice and it was attenuated by aminoguanidine. We conclude that the presence of IL-12/IL-23 during LPS-induced maturation influences the activation profile of DCs by a mechanism that is, only in part, IFN-c dependent.

show abstract

T-bet is required for optimal production of IFN-γ and antigen-specific T cell activation by dendritic cells

Cited by 236 publications

References 51 publications

Transcriptional control of human T‐BET expression: The role of Sp1

Transcriptional control of human T‐BET expression: The role of Sp1

Expression of T-bet by CD4 T Cells Is Essential for Resistance toSalmonellaInfection

Analysis of the activation profile of dendritic cells derived from the bone marrow of interleukin‐12/interleukin‐23‐deficient mice

Contact Info

Product

Resources

About