PD-1 Upregulated on Regulatory T Cells during Chronic Virus Infection Enhances the Suppression of CD8+ T Cell Immune Response via the Interaction with PD-L1 Expressed on CD8+ T Cells

Park, Hyojin; Park, Joon Seok; Jeong, Yun Hee; Son, Jimin; Ban, Young Ho; Lee, Byoung Hee; Chen, Lieping; Chang, Jun; Chung, Doo Hyun; Choi, Inhak; Ha, Sang Jun

doi:10.4049/jimmunol.1401936

Cited by 177 publications

(142 citation statements)

References 58 publications

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“…The role of exhaustion markers (particularly PD-1) on Treg function remains controversial, as it was demonstrated in malignant gliomas that PD-1 hi Treg was dysfunctional and produced IFNγ (26). Others have described that PD-1 expression is correlated with more suppressive Treg phenotypes in chronic viral infection (27). Our data, however, have clearly demonstrated a correlation between Treg suppression and exhaustion-marker expression.…”

Section: Discussioncontrasting

confidence: 56%

“…First, we focused on Tregs, given their well-established correlation with poor prognosis in various cancers, including HCC (23)(24)(25). Recent studies have also demonstrated the expression of exhaustion markers on Tregs, in particular PD-1, and their effect on Treg function (26,27). We then examined whether the Tregs expressed different immune exhaustion markers between the TIL, NIL, and PBMC groups.…”

Section: Lag-3mentioning

confidence: 99%

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Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses

Chew

Lai

Pan

et al. 2017

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

198

178

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The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8 + T cells (T RM s), resident natural killer cells (NK R s), and tumorassociated macrophages (TAMs). This finding was also validated with immunofluorescence staining on Foxp3Interestingly, Tregs and T RM s isolated from the TME expressed multiple markers for T-cell exhaustion, including PD-1, Lag-3, and Tim-3 compared with Tregs and T RM s isolated from the NTME. We found PD-1 + T RM s were the predominant T-cell subset responsive to anti-PD-1 treatment and significantly reduced in number with increasing HCC tumor progression. Furthermore, T-bet was identified as a key transcription factor, negatively correlated with PD-1 expression on memory CD8 + T cells, and the PD-1:T-bet ratio increased upon exposure to tumor antigens. Finally, transcriptomic analysis of tumor and adjacent nontumor tissues identified a chemotactic gradient for recruitment of TAMs and NK R s via CXCR3/ CXCL10 and CCR6/CCL20 pathways, respectively. Taken together, these data confirm the existence of an immunosuppressive gradient across the TME, NTME, and peripheral blood in primary HCC that manipulates the activation status of tumor-infiltrating leukocytes and renders them immunocompromised against tumor cells. By understanding the immunologic composition of this gradient, more effective immunotherapeutics for HCC may be designed.CyTOF | tumor microenvironment | regulatory T cells | resident memory T cells | hepatocellular carcinoma

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Section: Discussioncontrasting

confidence: 56%

Section: Lag-3mentioning

confidence: 99%

Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses

Chew

Lai

Pan

et al. 2017

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

198

178

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“…The function of PD-1 on the surface of Tregs is not entirely known (33,34). PD-1 hi Tregs in the TME in glioma patients have been found to be exhausted, yet capable of generating proinflammatory cytokines, such as IFN-γ (35).…”

Section: Discussionmentioning

confidence: 99%

Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer

Taylor¹,

Vick²,

Iglesia³

et al. 2017

Journal of Clinical Investigation

132

105

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“…During chronic infection, Tregs can suppress CD8 ϩ T cell activity in a contact-dependent manner (59). In this study, we investigated whether Foxp3 ϩ Tregs were in contact with and potentially inhibiting follicular SIV-specific CD8 ϩ T cell function.…”

Section: Foxp3 ؉ Cells Likely Inhibit Follicular and Extrafollicular mentioning

confidence: 99%

Simian Immunodeficiency Virus-Producing Cells in Follicles Are Partially Suppressed by CD8⁺CellsIn Vivo

Folkvord

Rakasz

et al. 2016

J Virol

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Human immunodeficiency virus (HIV)-and simian immunodeficiency virus (SIV)-specific CD8؉ T cells are typically largely excluded from lymphoid B cell follicles, where HIV-and SIV-producing cells are most highly concentrated, indicating that B cell follicles are somewhat of an immunoprivileged site. To gain insights into virus-specific follicular CD8؉ T cells, we determined the location and phenotype of follicular SIV-specific CD8 ؉ T cells in situ, the local relationship of these cells to Foxp3 ؉ cells, and the effects of CD8 depletion on levels of follicular SIV-producing cells in chronically SIV-infected rhesus macaques. We found that follicular SIV-specific CD8 ؉ T cells were able to migrate throughout follicular areas, including germinal centers. Many expressed PD-1, indicating that they may have been exhausted. A small subset was in direct contact with and likely inhibited by Foxp3؉ cells, and a few were themselves Foxp3 ؉ . In addition, subsets of follicular SIV-specific CD8 ؉ T cells expressed low to medium levels of perforin, and subsets were activated and proliferating. Importantly, after CD8 depletion, the number of SIVproducing cells increased in B cell follicles and extrafollicular areas, suggesting that follicular and extrafollicular CD8؉ T cells have a suppressive effect on SIV replication. Taken together, these results suggest that during chronic SIV infection, despite high levels of exhaustion and likely inhibition by

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PD-1 Upregulated on Regulatory T Cells during Chronic Virus Infection Enhances the Suppression of CD8+ T Cell Immune Response via the Interaction with PD-L1 Expressed on CD8+ T Cells

Cited by 177 publications

References 58 publications

Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses

Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses

Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer

Simian Immunodeficiency Virus-Producing Cells in Follicles Are Partially Suppressed by CD8⁺CellsIn Vivo

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PD-1 Upregulated on Regulatory T Cells during Chronic Virus Infection Enhances the Suppression of CD8+ T Cell Immune Response via the Interaction with PD-L1 Expressed on CD8+ T Cells

Cited by 177 publications

References 58 publications

Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses

Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses

Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer

Simian Immunodeficiency Virus-Producing Cells in Follicles Are Partially Suppressed by CD8+CellsIn Vivo

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Product

Resources

About

Simian Immunodeficiency Virus-Producing Cells in Follicles Are Partially Suppressed by CD8⁺CellsIn Vivo