Tim-3 Negatively Regulates Cytotoxicity in Exhausted CD8+ T Cells in HIV Infection

Sakhdari, Ali; Mujib, Shariq; Vali, Bahareh; Yue, Feng Yun; MacParland, Sonya A.; Clayton, Kiera; Jones, Richard Bradley; Liu, Junjun; Lee, Erika Yue; Benko, Erika; Kovacs, Colin; Gommerman, Jennifer L.; Kaul, Rupert; Ostrowski, Mario

doi:10.1371/journal.pone.0040146

Cited by 80 publications

(73 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with the aforementioned immune control in the presence of phenotypically exhausted T-cells, there is evidence that PD-1 high CD8 + T-cells can express similar or even elevated levels of cytotoxic molecules compared to cells with a less pronounced exhausted phenotype 37,[42][43][44][45] .…”

Section: Evidence That Functional T-cells Are Maintained In Chronic Isupporting

confidence: 52%

See 1 more Smart Citation

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

et al. 2014

View full text Add to dashboard Cite

Chronic viral infections and malignant tumours induce T cells that have a reduced ability to secrete effector cytokines and have upregulated expression of the inhibitory receptor PD1 (programmed cell death protein 1). These features have so far been considered to mark terminally differentiated 'exhausted' T cells. However, several recent clinical and experimental observations indicate that phenotypically exhausted T cells can still mediate a crucial level of pathogen or tumour control. In this Opinion article, we propose that the exhausted phenotype results from a differentiation process in which T cells stably adjust their effector capacity to the needs of chronic infection. We argue that this phenotype is optimized to cause minimal tissue damage while still mediating a critical level of pathogen control. In contrast to the presently held view of functional exhaustion, this new concept better reflects the pathophysiology and clinical manifestations of persisting infections, and it provides a rationale for emerging therapies that enhance T cell activity in chronic infection and cancer by blocking inhibitory receptors. Daniel T. Utzschneider Division of Immunology and Allergy of the Lausanne University Hospital (CHUV) and Swiss Vaccine Research Institute (SVRI), Lausanne, SwitzerlandDaniel Utzschneider is a PhD student of Dietmar Zehn. His research is focused on T-cell differentiation in chronic infection. Susanne G. Oberle Division of Immunology and Allergy of the Lausanne University Hospital (CHUV) and Swiss Vaccine Research Institute (SVRI), Lausanne, SwitzerlandSusanne Oberle is a PhD student of Dietmar Zehn. Her research interests are focused on investigating T-cell responses in acute and chronic infections. and it provides a rational for emerging therapies that enhance T-cell activity in chronic infection and cancer by blocking inhibitory receptors. Christian Münz PhD

show abstract

Section: Evidence That Functional T-cells Are Maintained In Chronic Isupporting

confidence: 52%

“… In vitro studies showed that the cytotoxic ability of HIV specific T-cells could be rescued by blocking Tim-3 45 .…”

Section: Malignant Diseasesmentioning

confidence: 99%

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The resulting persistent antigen levels drive a process called "T cell exhaustion," whereby responding T cells undergo hierarchical loss of their effector functions, including their ability to proliferate, their cytotoxic potential, and their ability to produce cytokines (1). Coinhibitory molecules, including programmed death receptor 1 (PD-1) (2-6), lymphocyte activation gene-3 (LAG-3) (5,7,8), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (9)(10)(11)(12), and T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) (4,(12)(13)(14) contribute to T cell exhaustion, reducing potentially harmful, persistent T cell activation. However, this also results in suboptimal HIV-specific responses and ultimately poor control of the virus.…”

mentioning

confidence: 99%

“…Furthermore, while sTim-3 has been correlated with graft-versus-host disease (32), it is unknown whether it can modulate immune pathways. Given Tim-3's role in HIV-associated T cell dysfunction (12)(13)(14), sTim-3 might play a role in modulating T cell responses during HIV infection. However, it is unclear what role sTim-3 may play, and further, the functional properties of soluble receptors may be dependent on the type of construct produced.…”

mentioning

confidence: 99%

Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8 ⁺ T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression

Clayton

Douglas-Vail

Rahman

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

Chronic HIV infection results in a loss of HIV-specific CD8؉ T cell effector function, termed "exhaustion," which is mediated, in part, by the membrane coinhibitory receptor T cell immunoglobulin mucin domain-3 (Tim-3). Like many other receptors, a soluble form of this protein has been described in human blood plasma. However, soluble Tim-3 (sTim-3) is poorly characterized, and its role in HIV disease is unknown. Here, we show that Tim-3 is shed from the surface of responding CD8 ؉ T cells by the matrix metalloproteinase ADAM10, producing a soluble form of the coinhibitory receptor. Despite previous reports in the mouse model, no alternatively spliced, soluble form of Tim-3 was observed in humans. Shed sTim-3 was found in human plasma and was significantly elevated during early and chronic untreated HIV infection, but it was not found differentially modulated in highly active antiretroviral therapy (HAART)-treated HIV-infected subjects or in elite controllers compared to HIV-uninfected subjects. Plasma sTim-3 levels were positively correlated with HIV load and negatively correlated with CD4 counts. Thus, plasma sTim-3 shedding correlated with HIV disease progression. Despite these correlations, we found that shedding Tim-3 did not improve the function of CD8 ؉ T cells in terms of gamma interferon production or prevent their apoptosis through galectin-9. Further characterization studies of sTim-3 function are needed to understand the contribution of sTim-3 in HIV disease pathogenesis, with implications for novel therapeutic interventions. IMPORTANCEDespite the overall success of HAART in slowing the progression to AIDS in HIV-infected subjects, chronic immune activation and T cell exhaustion contribute to the eventual deterioration of the immune system. Understanding these processes will aid in the development of interventions and therapeutics to be used in combination with HAART to slow or reverse this deterioration. Here, we show that a soluble form of T cell exhaustion associated coinhibitory molecule 3, sTim-3, is shed from the surface of T cells. Furthermore, sTim-3 is elevated in the plasma of treatment-naive subjects with acute or chronic HIV infection and is associated with markers of disease progression. This is the first study to characterize sTim-3 in human plasma, its source, and mechanism of production. While it is still unclear whether sTim-3 contributes to HIV pathogenesis, sTim-3 may represent a new correlate of HIV disease progression. D espite significant advances in the development of highly active antiretroviral therapy (HAART) to reduce viral replication in subjects chronically infected with human immunodeficiency virus type 1 (HIV), the immune system is incapable of completely eliminating the virus. The resulting persistent antigen levels drive a process called "T cell exhaustion," whereby responding T cells undergo hierarchical loss of their effector functions, including their ability to proliferate, their cytotoxic potential, and their ability to produce cytokines (1). Coinhibitor...

show abstract

“…Due to the generation and transmission of costimulatory signals, the apoptosis of target cells can regulate the immune response artificially (14)(15)(16). Tim-3 might act as a ligand for reverse transmission of signals to affect tumor immunity correspondingly (17,18). In order to investigate this new mechanism of Tim-3 molecules, hepatoma Hepa1-6 cell strain of ICR mouse was used to build a solid tumor model in thigh muscle to study the inhibitory effect of Tim-3 molecule on Hepa1-6 solid tumor and the influence on immune system of tumor bearing ICR mice.…”

Section: Introductionmentioning

confidence: 99%

Antitumor effect of membrane-type Tim-3 on hepatocellular carcinoma Hepa1-6 cells of ICR mice

et al. 2017

View full text Add to dashboard Cite

Abstract. In the present study, the inhibitory effect of transmembrane Tim-3 on hepatocellular carcinoma Hepa1-6 cells and the potential application of Tim-3 on immune system of Institute of Cancer Research (ICR) mice loaded with Hepa1-6 hepatocellular carcinoma was investigated. The animal model was established via inoculation of Hepa1-6 hepatocarcinoma cells at the hind thigh of ICR mice. Recombinant vector plasmids were transfected at the same site for gene therapy by injection to observe the inhibitory effect of Tim-3 on tumor growth. A panel of genes from tumor tissues at various time intervals was analyzed by reverse transcription-polymerase chain reaction. Flow cytometry was used to evaluate the proliferation and cytotoxicity of splenocytes after Tim-3 transfection. Synergistic effects of Tim-3 with tumor abnormal protein-1 (TAP1) was also studied. It was revealed that the growth of tumor was significantly suppressed after the transfection of Tim-3. In the presence of Tim-3, the proliferation of splenocytes and cytolysis in the early phase of tumor development was significantly enhanced, and this antitumor effect was further improved by the synergistic effect of Tim-3 with TAP1. Therefore, the membrane-type Tim-3 may behave as an effective immunoregulator to enhance antitumor immune responses. Furthermore the present findings suggest that antitumor immunity was improved by the combined effect of Tim-3 and TAP1.

show abstract

Tim-3 Negatively Regulates Cytotoxicity in Exhausted CD8+ T Cells in HIV Infection

Cited by 80 publications

References 73 publications

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8 ⁺ T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression

Antitumor effect of membrane-type Tim-3 on hepatocellular carcinoma Hepa1-6 cells of ICR mice

Contact Info

Product

Resources

About

Tim-3 Negatively Regulates Cytotoxicity in Exhausted CD8+ T Cells in HIV Infection

Cited by 80 publications

References 73 publications

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8 + T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression

Antitumor effect of membrane-type Tim-3 on hepatocellular carcinoma Hepa1-6 cells of ICR mice

Contact Info

Product

Resources

About

Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8 ⁺ T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression