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

Kragten, Natasja A. M.; Behr, Felix M.; Braga, Felipe A. Vieira; Remmerswaal, Ester B. M.; Wesselink, Thomas H.; Oja, Anna E.; Hombrink, Pleun; Kallies, Axel; Lier, René A. W. van; Stark, Regina; Gisbergen, Klaas P. J. M. van

doi:10.1002/eji.201847771

Cited by 68 publications

(68 citation statements)

References 51 publications

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“…S5B). Conversely, in concordance with previously described gene expression profiles (28,38), ITGB1 low CD8 + T cells associated with high gene expression levels of GZMK (Granzyme K), and the inhibitory receptor KLRB1 (CD161) ( Fig. 5 G, Right and Dataset S3).…”

Section: Restedsupporting

confidence: 90%

CD29 identifies IFN-γ–producing human CD8⁺T cells with an increased cytotoxic potential

Nicolet

Guislain

Alphen

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

101

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Cytotoxic CD8+T cells can effectively kill target cells by producing cytokines, chemokines, and granzymes. Expression of these effector molecules is however highly divergent, and tools that identify and preselect CD8+T cells with a cytotoxic expression profile are lacking. Human CD8+T cells can be divided into IFN-γ– and IL-2–producing cells. Unbiased transcriptomics and proteomics analysis on cytokine-producing fixed CD8+T cells revealed that IL-2+cells produce helper cytokines, and that IFN-γ+cells produce cytotoxic molecules. IFN-γ+T cells expressed the surface marker CD29 already prior to stimulation. CD29 also marked T cells with cytotoxic gene expression from different tissues in single-cell RNA-sequencing data. Notably, CD29+T cells maintained the cytotoxic phenotype during cell culture, suggesting a stable phenotype. Preselecting CD29-expressing MART1 TCR-engineered T cells potentiated the killing of target cells. We therefore propose that CD29 expression can help evaluate and select for potent therapeutic T cell products.

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Section: Restedsupporting

confidence: 90%

CD29 identifies IFN-γ–producing human CD8⁺T cells with an increased cytotoxic potential

Nicolet

Guislain

Alphen

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

101

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“…These results were confirmed at the mRNA level using qPCR (data not shown). The transcription factor Hobit (ZNF 683) has been shown to support the expression of granzyme B in highly differentiated T cells . Again, ZNF 683 expression was lowest in CD28 + CD57 − , intermediate in DP, significantly higher in DN compared to DP, and the highest in the CD28 − CD57 + subset (Table ).…”

Section: Resultsmentioning

confidence: 99%

CD28 and CD57 define four populations with distinct phenotypic properties within human CD8⁺ T cells

et al. 2019

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After repeated antigen exposure, both memory and terminally differentiated cells can be generated within CD8+ T cells. Although, during their differentiation, activated CD8+ T cells may first lose CD28, and CD28− cells may eventually express CD57 as a subsequent step, a population of CD28+CD57+(DP) CD8+ T cells can be identified in the peripheral blood. How this population is distinct from CD28−CD57−(DN) CD8+ T cells, and from the better characterized non‐activated/early‐activated CD28+CD57− and senescent‐like CD28−CD57+ CD8+ T cell subsets is currently unknown. Here, RNA expression of the four CD8+ T cell subsets isolated from human PBMCs was analyzed using microarrays. DN cells were more similar to “early” highly differentiated cells, with decreased TNF and IFN‐γ production, impaired DNA damage response and apoptosis. Conversely, increased apoptosis and expression of cytokines, co‐inhibitory, and chemokine receptors were found in DP cells. Higher levels of DP CD8+ T cells were observed 7 days after Hepatitis B vaccination, and decreased levels of DP cells were found in rheumatoid arthritis patients. More DP and DN CD8+ T cells were present in the bone marrow, in comparison with PBMCs. In summary, our results indicate that DP and DN cells are distinct CD8+ T cell subsets displaying defined properties.

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“…It could be that CD8 + T RM cells have a protective function in the BM, comparable to their role in liver, brain, and barrier tissues . Yet, in contrast to liver T RM , BM T RM cells did not contain preformed Granzyme B in their cytotoxic granules and are thus less likely to exert immediate cytotoxicity upon re‐challenge. Human BM CD8 + T cells with an effector memory phenotype, of which more than 70% expressed CD69, were also shown to contain much lower levels of Perforin and Granzyme B compared to paired samples of peripheral blood .…”

Section: Discussionmentioning

confidence: 99%

Peripheral and systemic antigens elicit an expandable pool of resident memory CD8⁺ T cells in the bone marrow

et al. 2019

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BM has been put forward as a major reservoir for memory CD8+ T cells. In order to fulfill that function, BM should “store” memory CD8+ T cells, which in biological terms would require these “stored” memory cells to be in disequilibrium with the circulatory pool. This issue is a matter of ongoing debate. Here, we unequivocally demonstrate that murine and human BM harbors a population of tissue‐resident memory CD8+ T (TRM) cells. These cells develop against various pathogens, independently of BM infection or local antigen recognition. BM CD8+ TRM cells share a transcriptional program with resident lymphoid cells in other tissues; they are polyfunctional cytokine producers and dependent on IL‐15, Blimp‐1, and Hobit. CD8+ TRM cells reside in the BM parenchyma, but are in close contact with the circulation. Moreover, this pool of resident T cells is not size‐restricted and expands upon peripheral antigenic re‐challenge. This works extends the role of the BM in the maintenance of CD8+ T cell memory to include the preservation of an expandable reservoir of functional, non‐recirculating memory CD8+ T cells, which develop in response to a large variety of peripheral antigens.

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

Cited by 68 publications

References 51 publications

CD29 identifies IFN-γ–producing human CD8⁺T cells with an increased cytotoxic potential

CD29 identifies IFN-γ–producing human CD8⁺T cells with an increased cytotoxic potential

CD28 and CD57 define four populations with distinct phenotypic properties within human CD8⁺ T cells

Peripheral and systemic antigens elicit an expandable pool of resident memory CD8⁺ T cells in the bone marrow

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

Cited by 68 publications

References 51 publications

CD29 identifies IFN-γ–producing human CD8+T cells with an increased cytotoxic potential

CD29 identifies IFN-γ–producing human CD8+T cells with an increased cytotoxic potential

CD28 and CD57 define four populations with distinct phenotypic properties within human CD8+ T cells

Peripheral and systemic antigens elicit an expandable pool of resident memory CD8+ T cells in the bone marrow

Contact Info

Product

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CD29 identifies IFN-γ–producing human CD8⁺T cells with an increased cytotoxic potential

CD29 identifies IFN-γ–producing human CD8⁺T cells with an increased cytotoxic potential

CD28 and CD57 define four populations with distinct phenotypic properties within human CD8⁺ T cells

Peripheral and systemic antigens elicit an expandable pool of resident memory CD8⁺ T cells in the bone marrow