The Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Induce the Expression of Programmed Death-1 and Its Ligands

Kinter, Audrey; Godbout, Emily; McNally, Jonathan P.; Sereti, Irini; Roby, Gregg; O’Shea, Marie A.; Fauci, Anthony S.

doi:10.4049/jimmunol.181.10.6738

Cited by 461 publications

(379 citation statements)

References 53 publications

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“…These studies did not examine Tim-3 or PD-1 expression on T cells. The gc cytokines IL-2, IL-7, IL-15, and IL-21 were also implicated in inducing PD-1 on the surface of CD4 + and CD8 + T cells (58). Although these gc cytokines are considered proinflammatory, our findings involving Tim-3 upregulation, as well as those of others regarding PD-1, suggest that they are also responsible for the activation of inhibitory pathways.…”

Section: Discussionmentioning

confidence: 40%

Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

Mujib

Jones

et al. 2012

The Journal of Immunology

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T cell Ig mucin domain-containing molecule 3 (Tim-3) is a glycoprotein found on the surface of a subset of CD8+ and Th1 CD4+ T cells. Elevated expression of Tim-3 on virus-specific T cells during chronic viral infections, such as HIV-1, hepatitis B virus, and hepatitis C virus, positively correlates with viral load. Tim-3+ cytotoxic T cells are dysfunctional and are unable to secrete effector cytokines, such as IFN-γ and TNF-α. In this study, we examined potential inducers of Tim-3 on primary human T cells. Direct HIV-1 infection of CD4+ T cells, or LPS, found to be elevated in HIV-1 infection, did not induce Tim-3 on T cells. Tim-3 was induced by the common γ-chain (γc) cytokines IL-2, IL-7, IL-15, and IL-21 but not IL-4, in an Ag-independent manner and was upregulated on primary T cells in response to TCR/CD28 costimulation, as well as γc cytokine stimulation with successive divisions. γc cytokine-induced Tim-3 was found on naive, effector, and memory subsets of T cells. Tim-3+ primary T cells were more prone to apoptosis, particularly upon treatment with galectin-9, a Tim-3 ligand, after cytokine withdrawal. The upregulation of Tim-3 could be blocked by the addition of a PI3K inhibitor, LY 294002. Thus, Tim-3 can be induced via TCR/CD28 costimulation and/or γc cytokines, likely through the PI3K pathway.

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Section: Discussionmentioning

confidence: 40%

Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

Mujib

Jones

et al. 2012

The Journal of Immunology

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“…Further analysis of the CD25 − population following influenza infection revealed that the expression of PD-1, another marker associated with TCR engagement, was upregulated but to a much lesser degree in this subset. It has been demonstrated that while PD-1 is indeed up-regulated markedly after TCR engagement, it can also be up-regulated in the presence of gamma-chain cytokines, although to a much lesser extent than following TCR engagement [46]. Subsequent analysis of PD-1 expression in the CD8 + CD25 + (TCR-triggered) and the CD8 + CD25…”

Section: Discussionmentioning

confidence: 99%

Influenza infection results in local expansion of memory CD8+ T cells with antigen non-specific phenotype and function

Sckisel

Tietze

Zamora

et al. 2013

Clinical and Experimental Immunology

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Summary Primary viral infections induce activation of CD8+ T cells responsible for effective resistance. We sought to characterize the nature of the CD8 + T cell expansion observed after primary viral infection with influenza. Infection of naive mice with different strains of influenza resulted in the rapid expansion of memory CD8 + T cells exhibiting a unique bystander phenotype with significant up-regulation of natural killer group 2D (NKG2D), but not CD25, on the CD44 high CD8+ T cells, suggesting an antigen non-specific phenotype. We further confirmed the non-specificity of this phenotype on ovalbuminspecific (OT-I) CD8 + T cells, which are not specific to influenza. These nonspecific CD8 + T cells also displayed increased lytic capabilities and were observed primarily in the lung. Thus, influenza infection was shown to induce a rapid, antigen non-specific memory T cell expansion which is restricted to the specific site of inflammation. In contrast, CD8 + T cells of a similar phenotype could be observed in other organs following administration of systemic agonistic anti-CD40 and interleukin-2 immunotherapy, demonstrating that bystander expansion in multiple sites is possible depending on whether the nature of activation is either acute or systemic. Finally, intranasal blockade of NKG2D resulted in a significant increase in viral replication early during the course of infection, suggesting that NKG2D is a critical mediator of anti-influenza responses prior to the initiation of adaptive immunity. These results characterize further the local bystander expansion of tissue-resident, memory CD8 + T cells which, due to their early induction, may play an important NKG2D-mediated, antigen non-specific role during the early stages of viral infection.

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“…This apparent paradox may be explained by the fact that B7H1 is engaged in the immune exhaustion process. Concurrent thyroiditis may provide a microenvironment enriched with IFNg, IL10, IL6, and common g-chain cytokines that are able to increase B7H1 expression (Kinter et al 2008, Wölfle et al 2011, Taube et al 2012.…”

Section: Discussionmentioning

confidence: 99%

Differentiated thyroid carcinomas may elude the immune system by B7H1 upregulation

Cunha¹,

Marcello²,

Morari³

et al. 2012

Endocrine-Related Cancer

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B7H1 is consistently associated with inhibition of the immune system in many solid tumors. However, there is no report about its impact on differentiated thyroid carcinoma (DTC) presentation, aggressiveness, or evolution. Aiming to investigate the role of B7H1 in DTC and correlate this protein with other tumor-infiltrating immune cells, we studied 407 thyroid nodule tissue samples including 293 from DTC patients, all managed according to a same standard protocol. In addition, we obtained 5 normal and 114 benign thyroid lesions. Eighteen out of the 253 papillary thyroid carcinomas were paired with respective metastatic lymph node tissues. B7H1 (CD274) protein expression was assessed by immunohistochemistry and the gene expression was quantified by real-time PCR. Malignant tissues displayed a more intense B7H1 staining and higher mRNA levels than benign tissues (both P!0.0001). We observed a positive linear correlation between higher age at diagnosis and B7H1 mRNA levels (PZ0.02896). Elevated levels of B7H1 protein were associated with the presence of CD4C, CD8C, CD20C, and FoxP3C lymphocytes (all P!0.05); tumor-associated macrophages (P!0.0001); and the presence of myeloid-derived suppressor cells (PZ0.03256). Stage II-IV patients presented higher B7H1 mRNA levels than stage I cases (PZ0.03522). On the contrary, a decreased expression of B7H1 protein was observed in lymph node metastasis (PZ0.0152). In conclusion, our data demonstrate that B7H1 expression is associated with features of aggressiveness, suggesting that this is an immune evasion mechanism of DTC cells.

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The Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Induce the Expression of Programmed Death-1 and Its Ligands

Cited by 461 publications

References 53 publications

Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

Influenza infection results in local expansion of memory CD8+ T cells with antigen non-specific phenotype and function

Differentiated thyroid carcinomas may elude the immune system by B7H1 upregulation

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