Diverse Roles for T-bet in the Effector Responses Required for Resistance to Infection

Pritchard, Gretchen Harms; Hall, Aisling O’Hara; Christian, David A.; Wagage, Sagie; Fang, Qun; Muallem, Gaia; John, Beena; Zaretsky, Arielle Glatman; Dunn, William G.; Perrigoue, Jacqueline; Reiner, Steven L.; Hunter, Christopher A.

doi:10.4049/jimmunol.1401617

Cited by 41 publications

(49 citation statements)

References 71 publications

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“…We challenged mice with Toxoplasma gondii , a parasitic infection known to be a major inducer of IFN-γ (Gazzinelli et al, 1993). Because T-bet deficient mice do not survive T. gondii infection due to the failure to systemically mount a protective Th1 response (Harms Pritchard et al, 2015), it was necessary to reconstitute Rag2 −/− mice with both wild type and Tbx21 −/− naïve T cells prior to infection. Consequently, these mice survived T. gondii infection upon challenge and importantly, both populations of T cells experienced the same inflammatory environment before transcriptome analysis (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells

et al. 2017

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Summary Host defense requires the specification of CD4+ helper T (Th) cells into distinct fates including Th1 cells that preferentially produce interferon-γ(IFN-γ) IFN-γ, a member of a large family of anti-pathogenic and anti-tumor IFNs, induces T-bet, a lineage defining transcription factor for Th1 cells, which in turn supports IFN-γ production in a feed-forward manner. Herein, we showed a cell intrinsic role of T-bet to influence how T cells perceive their secreted product in the environment. In the absence of T-bet, IFN-γ aberrantly induced a type I IFN transcriptomic program. T-bet preferentially repressed genes and pathways ordinarily activated by type I IFNs to ensure that its transcriptional response does not evoke an aberrant amplification of type I IFN signaling circuitry otherwise triggered by its own product. Thus, in addition to promoting Th1 effector commitment, T-bet acts as a repressor in differentiated Th1 cells to prevent abberant autocrine type I IFN and downstream signaling.

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Section: Resultsmentioning

confidence: 99%

The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells

et al. 2017

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“…Although we did not identify a functional defect, we did observe diminished expression of T-bet by Fut4/7 −/− CD4 + effector T cells in the lungs where their decreased recovery/survival was most pronounced. Although T-bet expression is associated with IFN-γ production by CD4 + effector T cells, the deficiency of this transcription factor does not necessarily impact IFN-γ production (51), which could account for our finding of comparable responses of primary WT and Fut4/7 −/− CD4 + effector T cells. Although T-bet as well as several other transcription factors have been extensively studied in CD8 + T cells which require T-bet expression for memory formation (52), few studies have addressed its role in CD4 + T cell differentiation.…”

Section: Discussionmentioning

confidence: 80%

Fucosyltransferase Induction during Influenza Virus Infection Is Required for the Generation of Functional Memory CD4+ T Cells

Tinoco

Carrette

Henriquez

et al. 2018

The Journal of Immunology

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T cells mediating influenza viral control are instructed in lymphoid and nonlymphoid tissues to differentiate into memory T cells that confer protective immunity. The mechanisms by which influenza virus-specific memory CD4+ T cells arise have been attributed to changes in transcription factors, cytokines and cytokine receptors, and metabolic programing. The molecules involved in these biosynthetic pathways including proteins and lipids are modified to varying degrees of glycosylation, fucosylation, sialation, and sulfation, which can alter their function. It is currently unknown how the glycome enzymatic machinery regulates CD4+ T cell effector and memory differentiation. In a murine model of influenza virus infection, we found that fucosyltransferase enzymatic activity was induced in effector and memory CD4+ T cells. Using CD4+ T cells deficient in the Fut4/7 enzymes that are expressed only in hematopoietic cells, we found decreased frequencies of effector cells with reduced expression of T-bet and NKG2A/C/E in the lungs during primary infection. Furthermore, Fut4/7−/− effector CD4+ T cells had reduced survival with no difference in proliferation or capacity for effector function. While Fut4/7−/− CD4+ T cells seeded the memory pool after primary infection, they failed to form tissue resident cells, were dysfunctional and were unable to re-expand after secondary infection. Our findings highlight an important regulatory axis mediated by cell-intrinsic fucosyltransferase activity in CD4+ T cell effectors that ensure the development of functional memory CD4+ T cells.

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“…We therefore hypothesized that Tbet may be required for ILC1 expansion after infection. As Tbx21 −/− mice succumb to T. gondii infection (Harms Pritchard et al, 2015), we studied WT: Tbx21 −/− mixed bone marrow chimeras. In spleens of both uninfected and infected chimeras, NK cells were present though they were biased towards WT origin ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Toxoplasma gondiiInfection Drives Conversion of NK Cells into ILC1s

Park¹,

Patel²,

Wang³

et al. 2019

Preprint

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22Innate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural 23 killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at 24 steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the 25 tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. 26Here we describe Toxoplasma gondii infection converts NK cells into cells resembling steady-state ILC1s 27 that are heterogeneous and distinct from both steady-state NK cells and ILC1s in uninfected mice. Most 28 toxoplasma-induced ILC1s were Eomes-dependent, indicating that NK cells can give rise to Eomes -Tbet-29 dependent ILC1-like cells that circulate widely and persist independent of ongoing infection. Moreover, 30these changes appear permanent, as supported by epigenetic analyses. Thus, these studies markedly 31 expand current concepts of NK cells, ILCs, and their potential conversion. 33Innate lymphoid cells (ILCs) comprise diverse populations. Like T and B cells, they are derived from 35 common lymphoid progenitors (CLPs) but do not undergo antigen receptor recombination (Spits and

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Diverse Roles for T-bet in the Effector Responses Required for Resistance to Infection

Cited by 41 publications

References 71 publications

The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells

The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells

Fucosyltransferase Induction during Influenza Virus Infection Is Required for the Generation of Functional Memory CD4+ T Cells

Toxoplasma gondiiInfection Drives Conversion of NK Cells into ILC1s

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