CRTAM determines the CD4+ cytotoxic T lymphocyte lineage

Takeuchi, Akihito; Badr, Mohamed El Sherif Gadelhaq; Miyauchi, Katsumi; Ishihara, Chitose; Onishi, Reiko; Guo, Zijin; Sasaki, Yoshiyuki; Ike, H.; Takumi, Akiko; Tsuji, Noriko M.; Murakami, Yoshinori; Katakai, Tomoya; Kubo, Masato; Saito, Takashi

doi:10.1084/jem.20150519

Cited by 172 publications

(174 citation statements)

References 51 publications

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“…CRTAM + CD4 + T cells secrete IFN‐γ, express CTL‐related genes such as Eomes, granzyme B and perforin, and exhibit cytotoxic function. Accordingly, ectopic expression of CRTAM in T cells induces the production of IFN‐γ, expression of CTL‐related genes, and cytotoxic activity …”

Section: Discussionsupporting

confidence: 70%

CRTAM+ NK cells endowed with suppressor properties arise in leukemic bone marrow

Ramírez-Ramírez

Padilla-Castañeda

Galán-Enríquez

et al. 2019

Journal of Leukocyte Biology

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Due to their increasing rates of morbidity and mortality, childhood malignancies are considered a global health priority, with acute lymphoblastic leukemias (ALLs) showing the highest incidence worldwide. Control of malignant clone emergence and the subsequent normal‐leukemic hematopoietic cell out‐competition require antitumor monitoring mechanisms. Investigation of cancer surveillance innate cells may be critical to understand the mechanisms contributing in either disease progression or relapse, and to promote displacement of leukemic hematopoiesis by the normal counterpart. We report here that NK cell production is less and low hematopoietic progenitor numbers contribute to this defect. By investigating the expression of the activation molecule class I restricted T‐cell associated molecule (CRTAM) along the hematopoietic lineage differentiation pathway, we have identified lymphoid precursor populations coexpressing CD34, CD56/CD3/CD19, and CRTAM as the earliest developmental stage where activation may take place in specialized niches that display the ligand nectin‐like‐2. Of note, bone marrow (BM) from patients with ALL revealed high contents of preactivated CD56high NK cells expressing CRTAM and endowed with an exhaustion‐like phenotype and the functional capability of producing IL‐10 and TGF‐β in vitro. Our findings suggest, for the first time, that the tumor microenvironment in ALL directly contribute to exhaustion of NK cell functions by the CRTAM/Necl‐2 interaction, and that the potential regulatory role of exhausted‐like NK cells may favor malignant progression at the expense of anti‐tumor responses. Phenotypic and functional identity of this unique suppressor‐like NK cell population within the leukemic BM would be of special interest for the pathobiology of ALL and development of targeting strategies.

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Section: Discussionsupporting

confidence: 70%

CRTAM+ NK cells endowed with suppressor properties arise in leukemic bone marrow

Ramírez-Ramírez

Padilla-Castañeda

Galán-Enríquez

et al. 2019

Journal of Leukocyte Biology

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“…The clonally expanded cells had a higher mean expression of cytotoxic signature genes (T EMRA -enriched gene set) (Fig. 2, C and D), suggestive of greater effector potential (6, 25, 36). …”

Section: Resultsmentioning

confidence: 97%

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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“…Our analysis confirmed the relative loss of Zbtb7b expression (encoding ThPOK) and acquisition of Runx3 expression, considered responsible for the reprogramming of CD4 + CTLs (Mucida et al., 2013, Reis et al., 2013). However, despite acquiring Runx3 expression under the conditions we have examined, CD4 + CTLs did not express other CD8 + lineage-related genes, such as Cd8a or Crtam , previously observed in CD4 + CTLs in other conditions (Mucida et al., 2013, Reis et al., 2013, Takeuchi et al., 2016). It is possible that acquisition of CD8 + lineage-related characteristics is not as extensive in splenic CD4 + CTLs as in intestine intraepithelial CD4 + CTLs.…”

Section: Discussionmentioning

confidence: 99%

Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus

et al. 2016

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SummaryCD4+ T cells develop distinct and often contrasting helper, regulatory, or cytotoxic activities. Typically a property of CD8+ T cells, granzyme-mediated cytotoxic T cell (CTL) potential is also exerted by CD4+ T cells. However, the conditions that induce CD4+ CTLs are not entirely understood. Using single-cell transcriptional profiling, we uncover a unique signature of Granzyme B (GzmB)+ CD4+ CTLs, which distinguishes them from other CD4+ T helper (Th) cells, including Th1 cells, and strongly contrasts with the follicular helper T (Tfh) cell signature. The balance between CD4+ CTL and Tfh differentiation heavily depends on the class of infecting virus and is jointly regulated by the Tfh-related transcription factors Bcl6 and Tcf7 (encoding TCF-1) and by the expression of the inhibitory receptors PD-1 and LAG3. This unique profile of CD4+ CTLs offers targets for their study, and its antagonism by the Tfh program separates CD4+ T cells with either helper or killer functions.

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CRTAM determines the CD4+ cytotoxic T lymphocyte lineage

Abstract: Takeuchi et al. demonstrate that CRTAM identifies CD4 T cells with cytotoxic function, and present new insights into CD4+CTL development.

Cited by 172 publications

References 51 publications

CRTAM+ NK cells endowed with suppressor properties arise in leukemic bone marrow

CRTAM+ NK cells endowed with suppressor properties arise in leukemic bone marrow

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

Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus

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CRTAM determines the CD4+ cytotoxic T lymphocyte lineage

Abstract: Takeuchi et al. demonstrate that CRTAM identifies CD4 T cells with cytotoxic function, and present new insights into CD4+CTL development.

Cited by 172 publications

References 51 publications

CRTAM+ NK cells endowed with suppressor properties arise in leukemic bone marrow

CRTAM+ NK cells endowed with suppressor properties arise in leukemic bone marrow

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

Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus

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