The Transcription Factor Hobit Identifies Human Cytotoxic CD4+ T Cells

Oja, Anna E.; Braga, Felipe A. Vieira; Remmerswaal, Ester B. M.; Kragten, Natasja A. M.; Hertoghs, Kirsten M. L.; Zuo, Jianmin; Moss, Paul; Lier, René A. W. van; Gisbergen, Klaas P. J. M. van; Hombrink, Pleun

doi:10.3389/fimmu.2017.00325

Cited by 57 publications

(78 citation statements)

References 28 publications

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“…1, B and C). ZNF683 has recently been shown to identify human CD4-CTLs (24), and Eomes and T-bet appear to be important in the development of CD4-CTLs (27, 28). These results confirm that human CD4-CTLs are highly enriched in the T EMRA subset.…”

Section: Resultsmentioning

confidence: 99%

“…4E). The role of ZNF683 (Hobit) (24, 46, 49) and other transcripts ( PRSS23 , SPON2 , and TCF7 ) (47, 48) in the survival and long-term persistence of these high cytotoxic terminal effector cells deserves further investigation (45). …”

Section: Resultsmentioning

confidence: 99%

“…However, we observed marked clonal expansion of CD4-CTL effectors in several donors, suggesting that, compared with other conventional T H effector cells, different molecular mechanisms may operate in CD4-CTL effectors to promote their long-term survival. IL-7R − T EMRA CD4-CTL effectors highly expressed several molecules that are linked to cell survival such as CRTAM , ZNF683 (Hobit), PRSS23 , SPON2 , and TCF7 (encodes TCF1) (24, 46–51). Therefore, we hypothesize that these candidate molecules are likely to confer long-term survival properties to CD4-CTL effectors, which warrants further functional investigation in model organisms.…”

Section: Discussionmentioning

confidence: 99%

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Precursors of human CD4 ⁺ cytotoxic T lymphocytes identified by single-cell transcriptome analysis

et al. 2018

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CD4+ cytotoxic T lymphocytes (CD4-CTLs) have been reported to play a protective role in several viral infections. However, little is known in humans about the biology of CD4-CTL generation, their functional properties, and heterogeneity, especially in relation to other well-described CD4+ memory T cell subsets. We performed single-cell RNA sequencing in more than 9000 cells to unravel CD4-CTL heterogeneity, transcriptional profile, and clonality in humans. Single-cell differential gene expression analysis revealed a spectrum of known transcripts, including several linked to cytotoxic and costimulatory function that are expressed at higher levels in the TEMRA (effector memory T cells expressing CD45RA) subset, which is highly enriched for CD4-CTLs, compared with CD4+ T cells in the central memory (TCM) and effector memory (TEM) subsets. Simultaneous T cell antigen receptor (TCR) analysis in single cells and bulk subsets revealed that CD4-TEMRA cells show marked clonal expansion compared with TCM and TEM cells and that most of CD4-TEMRA were dengue virus (DENV)–specific in donors with previous DENV infection. The profile of CD4-TEMRA was highly heterogeneous across donors, with four distinct clusters identified by the single-cell analysis. We identified distinct clusters of CD4-CTL effector and precursor cells in the TEMRA subset; the precursor cells shared TCR clonotypes with CD4-CTL effectors and were distinguished by high expression of the interleukin-7 receptor. Our identification of a CD4-CTL precursor population may allow further investigation of how CD4-CTLs arise in humans and, thus, could provide insights into the mechanisms that may be used to generate durable and effective CD4-CTL immunity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Precursors of human CD4 ⁺ cytotoxic T lymphocytes identified by single-cell transcriptome analysis

et al. 2018

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“…We have previously published that human Hobit is expressed in circulating populations of NK cells and antigen-experienced CD4 and CD8 T cells [20,34] in contrast to murine Hobit, which is specifically expressed in Trm and other resident lymphocytes including ILC1 and NKT cells [19]. We speculate that divergent evolutionary pressures by distinct mouse and human pathogens may have driven the unique expression patterns of Hobit in mice and humans.…”

Section: Discussionmentioning

confidence: 96%

Blimp‐1 induces and Hobit maintains the cytotoxic mediator granzyme B in CD8 T cells

et al. 2018

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CD8 T cells acquire cytotoxic molecules including granzyme B during effector differentiation. Both tissue-resident memory CD8 T cells (Trm) and circulating CD45RA effector-type T cells (Temra) cells have the ability to retain granzyme B protein expression into the memory phase, but it is unclear how this persistence of cytolytic activity is regulated during steady state. Previously, we have described that the transcriptional regulators Hobit and Blimp-1 have overlapping target genes that include granzyme B, but their impact on the regulation of cytotoxicity in Trm and Temra cells during homeostasis has remained unclear. We examined the expression regulation of Hobit and Blimp-1 in murine and human CD8 T-cells to determine their timeframe of activity. While Blimp-1 mRNA was expressed throughout effector and memory T cells, Blimp-1 protein, was only transiently expressed during the effector stage. In contrast, Hobit mRNA and protein expression was stably maintained during quiescence, but downregulated after activation. Notably, Blimp-1 was required for expression of granzyme B in murine effector T cells and Trm, while Hobit specifically regulated granzyme B in murine Trm during the memory phase. These findings suggest that Blimp-1 initiates cytotoxic effector function and that Hobit maintains cytotoxicity in a deployment-ready modus in Trm.

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“…However, it is also possible that CD4 þ CTLs may comprise a distinct, independent subset of CD4 þ effector T cells that differ from conventional Th1 cells (10). Indeed, several recent reports have identified specific markers for CD4 þ CTLs (11)(12)(13)(14). Interestingly, Eomes is expressed in many of the cells expressing these markers, as well as in other CD4 þ T cells with cytolytic properties (15)(16)(17)(18); these findings suggested that Eomes governs development of CD4 þ CTLs and that Eomes expression is a marker for CD4 þ CTLs.…”

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confidence: 99%

Role of T‐bet, the master regulator of Th1 cells, in the cytotoxicity of murine CD4⁺ T cells

Eshima

Misawa

Ohashi

et al. 2018

Microbiology and Immunology

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Although CD4 T cells are generally regarded as helper T cells, some activated CD4 T cells have cytotoxic properties. Given that CD4 cytotoxic T lymphocytes (CTLs) often secrete IFN-γ, CTL activity among CD4 T cells may be attributable to Th1 cells, where a T-box family molecule, T-bet serves as the "master regulator". However, although the essential contribution of T-bet to expression of IFN-γ has been well-documented, it remains unclear whether T-bet is involved in CD4 T cell-mediated cytotoxicity. In this study, to investigate the ability of T-bet to confer cytolytic activity on CD4 T cells, the T-bet gene (Tbx21) was introduced into non-cytocidal CD4 T cell lines and their cytolytic function analyzed. Up-regulation of FasL (CD178), which provided the transfectant with cytotoxicity, was observed in Tbx21transfected CD4 T cells but not in untransfected parental cells. In one cell line, T-bet transduction also induced perforin gene (Prf1) expression and Tbx21 transfectants efficiently killed Fas target cells. Although T-bet was found to repress up-regulation of CD40L (CD154), which controls FasL-mediated cytolysis, the extent of CD40L up-regulation on in vitro-differentiated Th1 cells was similar to that on Th2 cells, suggesting the existence of a compensatory mechanism. These results collectively indicate that T-bet may be involved in the expression of genes, such as FasL and Prf1, which confer cytotoxicity on Th1 cells.

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The Transcription Factor Hobit Identifies Human Cytotoxic CD4+ T Cells

Cited by 57 publications

References 28 publications

Precursors of human CD4 ⁺ cytotoxic T lymphocytes identified by single-cell transcriptome analysis

Precursors of human CD4 ⁺ cytotoxic T lymphocytes identified by single-cell transcriptome analysis

Blimp‐1 induces and Hobit maintains the cytotoxic mediator granzyme B in CD8 T cells

Role of T‐bet, the master regulator of Th1 cells, in the cytotoxicity of murine CD4⁺ T cells

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The Transcription Factor Hobit Identifies Human Cytotoxic CD4+ T Cells

Cited by 57 publications

References 28 publications

Precursors of human CD4 + cytotoxic T lymphocytes identified by single-cell transcriptome analysis

Precursors of human CD4 + cytotoxic T lymphocytes identified by single-cell transcriptome analysis

Blimp‐1 induces and Hobit maintains the cytotoxic mediator granzyme B in CD8 T cells

Role of T‐bet, the master regulator of Th1 cells, in the cytotoxicity of murine CD4+ T cells

Contact Info

Product

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Precursors of human CD4 ⁺ cytotoxic T lymphocytes identified by single-cell transcriptome analysis

Precursors of human CD4 ⁺ cytotoxic T lymphocytes identified by single-cell transcriptome analysis

Role of T‐bet, the master regulator of Th1 cells, in the cytotoxicity of murine CD4⁺ T cells