CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature

ABSTRACTCD4+T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4+T cell functions beyond helper effects have been described, and a role for cytolytic CD4+T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4+T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4+T cells revealed a distinct transcriptional signature compared to Th1 CD4+cells but shared similar features with HIV-specific cytolytic CD8+T cells. Furthermore, HIV-specific cytolytic CD4+T cells showed comparable killing activity relative to HIV-specific CD8+T cells and worked cooperatively in the elimination of virally infected cells. Interestingly, we found that cytolytic CD4+T cells emerge early during acute HIV infection and tightly follow acute viral load trajectory. This emergence was associated to the early viral set point, suggesting an involvement in early control, in spite of CD4 T cell susceptibility to HIV infection. Our data suggest cytolytic CD4+T cells as an independent subset distinct from Th1 cells that show combined activity with CD8+T cells in the long-term control of HIV infection.IMPORTANCEThe ability of the immune system to control chronic HIV infection is of critical interest to both vaccine design and therapeutic approaches. Much research has focused on the effect of the ability of CD8+T cells to control the virus, while CD4+T cells have been overlooked as effectors in HIV control due to the fact that they are preferentially infected. We show here that a subset of HIV-specific CD4+T cells cooperate in the cytolytic control of HIV replication. Moreover, these cells represent a distinct subset of CD4+T cells showing significant transcriptional and phenotypic differences compared to HIV-specific Th1 cells but with similarities to CD8+T cells. These findings are important for our understanding of HIV immunopathology.

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EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4+ T cells in chronic lymphocytic leukemia

Leukemia ◽

10.1038/s41375-021-01136-1 ◽

2021 ◽

Author(s):

Philipp M. Roessner ◽

Laura Llaó Cid ◽

Ekaterina Lupar ◽

Tobias Roider ◽

Marie Bordas ◽

...

Keyword(s):

T Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Cytotoxic Activities ◽

Dependent Manner ◽

Transcriptional Signature ◽

And Control ◽

Regulatory Type

AbstractThe transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4+ T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4+ T cells in lymph nodes (LNs) of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive IL-10 expression, but rather controls a unique transcriptional signature in CD4+ T cells, that is enriched in genes typical for T regulatory type 1 (TR1) cells. The TR1 cell identity of these CD4+ T cells was supported by their expression of interferon gamma and IL-10, as well as inhibitory receptors including PD-1. TR1 cells with cytotoxic capacity accumulate also in Eµ-TCL1 mice that develop CLL-like disease. Whereas wild-type CD4+ T cells control TCL1 leukemia development after adoptive transfer in leukopenic Rag2−/− mice, EOMES-deficient CD4+ T cells failed to do so. We further show that TR1 cell-mediated control of TCL1 leukemia requires IL-10 receptor (IL-10R) signaling, as Il10rb-deficient CD4+ T cells showed impaired antileukemia activity. Altogether, our data demonstrate that EOMES is indispensable for the development of IL-10-expressing, cytotoxic TR1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner.

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Faculty Opinions recommendation of A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717957715.793462567 ◽

2012 ◽

Author(s):

E Charles Snow

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Genetic Switch ◽

Transcriptional Signature

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Dynamic expression of Id3 defines the stepwise differentiation of tissue-resident regulatory T cells

10.1101/359687 ◽

2018 ◽

Author(s):

Jenna M. Sullivan ◽

Barbara Höllbacher ◽

Daniel J. Campbell

Keyword(s):

T Cells ◽

Protein Function ◽

Effector T Cells ◽

Lymphoid Tissues ◽

Step Process ◽

Transcriptional Signature ◽

E Protein ◽

Dynamic Expression ◽

And Function ◽

Functionally Diverse

AbstractFoxp3+ regulatory T (TR) cells are phenotypically and functionally diverse, and broadly distributed in lymphoid and non-lymphoid tissues. However, the pathways guiding the differentiation of tissue-resident TR populations have not been well defined. By regulating E-protein function, Id3 controls the differentiation of CD8+ effector T cells and is essential for TR maintenance and function. We show that dynamic expression of Id3 helps define three distinct TR populations, Id3+CD62LhiCD44lo central (c)TR, Id3+CD62LloCD44hi effector (e)TR and Id3- eTR. Adoptive transfer experiments and transcriptome analyses support a stepwise model of differentiation from Id3+ cTR to Id3+ eTR to Id3- eTR. Furthermore, Id3- eTR have high expression of functional inhibitory markers and a transcriptional signature of tissue-resident TR. Accordingl Id3- eTR are highly enriched in non-lymphoid organs, but virtually absent from blood and lymph Thus, we propose that tissue-resident TR develop in a multi-step process associated with Id3 downregulation.

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Human regulatory T cells at the maternal-fetal interface show functional site-specific adaptation with tumor-infiltrating-like features

10.1101/820753 ◽

2019 ◽

Cited By ~ 3

Author(s):

Judith Wienke ◽

Laura Brouwers ◽

Leone van der Burg ◽

Michal Mokry ◽

Rianne C. Scholman ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Human Tumor ◽

Control Site ◽

Transcriptional Profile ◽

Functional Adaptation ◽

Immune Checkpoints ◽

Site Specific ◽

Transcriptional Signature ◽

Maternal Fetal Interface

AbstractObjectivesRegulatory T cells (Tregs) are crucial for maintaining immune tolerance against the semi-allogeneic fetus during pregnancy. Since their functional profile at the human maternal-fetal interface is still elusive, we investigated the transcriptional profile and functional adaptation of human uterine Tregs (uTregs) during pregnancy.MethodsBlood and uterine biopsies from the placental bed (=maternal-fetal interface) and incision site (=control), were obtained from women with uneventful pregnancies undergoing primary Caesarean section. Tregs and CD4+ non-Tregs (Tconv) were isolated for transcriptomic profiling by Cel-Seq2. Results were validated on protein and single cell level by flow cytometry.ResultsPlacental bed uterine Tregs (uTregs) showed elevated expression of Treg signature markers compared to blood Tregs, including FOXP3, CTLA4 and TIGIT. The uTreg transcriptional profile was indicative of late-stage effector Treg differentiation and chronic activation with high expression of immune checkpoints GITR, TNFR2, OX-40, 4-1BB, genes associated with suppressive capacity (CTLA4, HAVCR2, IL10, IL2RA, LAYN, PDCD1), activation (HLA-DR, LRRC32), and transcription factors MAF, PRDM1, BATF, and VDR. uTregs mirrored uTconv Th1 polarization, and characteristics indicating tissue-residency, including high CD69, CCR1, and CXCR6. The particular transcriptional signature of placental bed uTregs overlapped strongly with the specialized profile of human tumor-infiltrating Tregs, and, remarkably, was more pronounced at the placental bed than uterine control site.ConclusionuTregs at the maternal-fetal interface acquire a highly differentiated effector Treg profile similar to tumor-infiltrating Tregs, which is locally enriched compared to a distant uterine site. This introduces the novel concept of site-specific transcriptional adaptation of human Tregs within one organ.

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Liver-resident memory CD8+ T cells in chronic viral infection exhibit a unique transcriptional signature and are not terminally exhausted

10.1055/s-0038-1677249 ◽

2019 ◽

Author(s):

M Bosch ◽

N Kallin ◽

K Manske ◽

S Donakonda ◽

D Wohlleber ◽

...

Keyword(s):

T Cells ◽

Viral Infection ◽

Cd8 T Cells ◽

Chronic Viral Infection ◽

Memory Cd8 T Cells ◽

Transcriptional Signature

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Transcriptional signature of resting-memory CD4 T cells differentiates spontaneous from treatment-induced HIV control

Journal of Molecular Medicine ◽

10.1007/s00109-020-01930-x ◽

2020 ◽

Vol 98 (8) ◽

pp. 1093-1105

Author(s):

Marcial García ◽

Luis López-Fernández ◽

Pablo Mínguez ◽

Sara Morón-López ◽

Clara Restrepo ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Transcriptional Signature ◽

Memory Cd4 T Cells

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Immuno-PET identifies the myeloid compartment as a key contributor to the outcome of the antitumor response under PD-1 blockade

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1905005116 ◽

2019 ◽

Vol 116 (34) ◽

pp. 16971-16980 ◽

Cited By ~ 15

Author(s):

Mohammad Rashidian ◽

Martin W. LaFleur ◽

Vincent L. Verschoor ◽

Anushka Dongre ◽

Yun Zhang ◽

...

Keyword(s):

T Cells ◽

Single Cell ◽

Rna Sequencing ◽

Myeloid Cells ◽

Single Domain Antibody ◽

Transcriptional Signature ◽

Positron Emission ◽

Tumor Periphery ◽

Wide Range ◽

Single Cell Rna Sequencing

Immunotherapy using checkpoint-blocking antibodies against PD-1 has produced impressive results in a wide range of cancers. However, the response remains heterogeneous among patients. We used noninvasive immuno-positron emission tomography (PET), using 89Zr-labeled PEGylated single-domain antibody fragments (nanobodies or VHHs), to explore the dynamics and distribution of intratumoral CD8+ T cells and CD11b+ myeloid cells in response to anti–PD-1 treatment in the MC38 colorectal mouse adenocarcinoma model. Responding and nonresponding tumors showed consistent differences in the distribution of CD8+ and CD11b+ cells. Anti–PD-1 treatment mobilized CD8+ T cells from the tumor periphery to a more central location. Only those tumors fully infiltrated by CD8+ T cells went on to complete resolution. All tumors contained CD11b+ myeloid cells from the outset of treatment, with later recruitment of additional CD11b+ cells. As tumors grew, the distribution of intratumoral CD11b+ cells became more heterogeneous. Shrinkage of tumors in responders correlated with an increase in the CD11b+ population in the center of the tumors. The changes in distribution of CD8+ and CD11b+ cells, as assessed by PET, served as biomarkers to gauge the efficacy of anti–PD-1 treatment. Single-cell RNA sequencing of RNA from intratumoral CD45+ cells showed that CD11b+ cells in responders and nonresponders were markedly different. The responders exhibited a dominant population of macrophages with an M1-like signature, while the CD45+ population in the nonresponders displayed an M2-like transcriptional signature. Thus, by using immuno-PET and single-cell RNA sequencing, we show that anti–PD-1 treatment not only affects interactions of CD8+ T cells with the tumor but also impacts the intratumoral myeloid compartment.

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