Correlation Between TIGIT Expression on CD8+ T Cells and Higher Cytotoxic Capacity

Blažková, Jana; Huiting, Erin; Boddapati, Arun K.; Shi, Victoria; Whitehead, Emily J; Justement, J. Shawn; Nordstrom, Jeffrey L.; Moir, Susan; Lack, Justin; Chun, Tae‐Wook

doi:10.1093/infdis/jiab155

Cited by 14 publications

(14 citation statements)

References 14 publications

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“…These observations suggested that CD8 + T cells from PLWH had intact lytic function despite high levels of TIGIT. This is consistent with a recent study that showed that TIGIT expression in CD8 + T cells correlated with cytotoxic capacity in PLWH and thus is not necessarily an indicator of exhaustion 33 . ImmTAV molecules enable polyclonal CD8 + T cells from PLWH to form lytic immune synapses.…”

Section: Resultssupporting

confidence: 93%

“…Since CD39 and TIGIT upregulation are reported to be features of exhausted T cells, the detection of lytic activity in this context appears paradoxical. However, a recent report from Blazkova et al noted that the frequency of TIGIT + cells was positively correlated with the lytic capacity of CD8 + T cells from aviremic (ART-treated) individuals when redirected by an HIV-specific DART, calling into question whether TIGIT expression can be used to define a state of functional exhaustion 33 . Furthermore, CD39 upregulation could reflect recent T cell activation.…”

Section: Discussionmentioning

confidence: 99%

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Immune mobilising T cell receptors redirect polyclonal CD8+ T cells in chronic HIV infection to form immunological synapses

Wallace

Kopycinski

Yang

et al. 2022

Sci Rep

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T cell exhaustion develops in human immunodeficiency virus (HIV) infection due to chronic viral antigenic stimulation. This adaptive response primarily affects virus-specific CD8+ T cells, which may remain dysfunctional despite viral load-reducing antiretroviral therapy; however, abnormalities may also be evident in non-HIV-specific populations. Both could limit the efficacy of cell therapies against viral reservoirs. Here, we show that bulk (polyclonal) CD8+ T cells from people living with HIV (PLWH) express proposed markers of dysfunctional HIV-specific T cells at high levels yet form lytic immunological synapses (IS) and eliminate primary resting infected (HIV Gaglo) CD4+ T cells, when redirected by potent bispecific T cell-retargeting molecules, Immune mobilising monoclonal T cell receptors (TCR) Against Virus (ImmTAV). While PLWH CD8+ T cells are functionally impaired when compared to CD8+ T cells from HIV-naïve donors, ImmTAV redirection enables them to eliminate Gaglo CD4+ T cells that are insensitive to autologous HIV-specific cytolytic T cells. ImmTAV molecules may therefore be able to target HIV reservoirs, which represent a major barrier to a cure.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Immune mobilising T cell receptors redirect polyclonal CD8+ T cells in chronic HIV infection to form immunological synapses

Wallace

Kopycinski

Yang

et al. 2022

Sci Rep

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“…Also, TIGIT was up-regulated in both T cell subsets in the presence of LDL high by trend. Although the upregulation of TIGIT can exert immunosuppressive features in tumor immunity (83, 84), literature revealed TIGIT + CD8 + subsets with cytotoxic properties (85).…”

Section: Discussionmentioning

confidence: 99%

Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model

et al. 2023

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IntroductionThe discovery of immune checkpoints and the development of their specific inhibitors was acclaimed as a major breakthrough in cancer therapy. However, only a limited patient cohort shows sufficient response to therapy. Hence, there is a need for identifying new checkpoints and predictive biomarkers with the objective of overcoming immune escape and resistance to treatment. Having been associated with both, treatment response and failure, LDL seems to be a double-edged sword in anti-PD1 immunotherapy. Being embedded into complex metabolic conditions, the impact of LDL on distinct immune cells has not been sufficiently addressed. Revealing the effects of LDL on T cell performance in tumor immunity may enable individual treatment adjustments in order to enhance the response to routinely administered immunotherapies in different patient populations. The object of this work was to investigate the effect of LDL on T cell activation and tumor immunity in-vitro. MethodsExperiments were performed with different LDL dosages (LDLlow = 50 μg/ml and LDLhigh = 200 μg/ml) referring to medium control. T cell phenotype, cytokines and metabolism were analyzed. The functional relevance of our findings was studied in a HCT116 spheroid model in the context of anti-PD-1 blockade.ResultsThe key points of our findings showed that LDLhigh skewed the CD4+ T cell subset into a central memory-like phenotype, enhanced the expression of the co-stimulatory marker CD154 (CD40L) and significantly reduced secretion of IL-10. The exhaustion markers PD-1 and LAG-3 were downregulated on both T cell subsets and phenotypical changes were associated with a balanced T cell metabolism, in particular with a significant decrease of reactive oxygen species (ROS). T cell transfer into a HCT116 spheroid model resulted in a significant reduction of the spheroid viability in presence of an anti-PD-1 antibody combined with LDLhigh.DiscussionFurther research needs to be conducted to fully understand the impact of LDL on T cells in tumor immunity and moreover, to also unravel LDL effects on other lymphocytes and myeloid cells for improving anti-PD-1 immunotherapy. The reason for improved response might be a resilient, less exhausted phenotype with balanced ROS levels.

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“…TIGIT can participate in splenic immune responses induced in many chronic infectious diseases (Wykes and Lewin, 2018;Blazkova et al, 2021). Virological studies showed that the proportion of TIGIT + CD8 + T cells were increased significantly in HIV patients, which was positively correlated with plasma viral load and disease progression.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Expressions of TIGIT on Splenic T Cells and TIGIT-Mediated Splenic T Cell Dysfunction of Mice With Chronic Toxoplasma gondii Infection

Zhang

et al. 2021

Front. Microbiol.

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As an immunosuppressive receptor, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) play a critical part in cellular immune regulation mediated by pathogen infection. Whereas, TIGIT expression on splenic T cells in hosts infected with Toxoplasma gondii cysts has not been studied. In this study, we detected TIGIT expression and the changes of immune function in the spleen by flow cytometry and real-time PCR (RT-PCR). We found that TIGIT expression on splenic T cells increased significantly post infection. At the same time, splenic TIGIT+TCM cells were activated and transformed into TIGIT+TEM cells during the infection, and the cytotoxicity of TIGIT+ T cells was reduced in the later stage of infection. This study shows that chronic T. gondii infection can upregulate TIGIT expression on the surface of T cells and affect immune cell function.

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Correlation Between TIGIT Expression on CD8+ T Cells and Higher Cytotoxic Capacity

Cited by 14 publications

References 14 publications

Immune mobilising T cell receptors redirect polyclonal CD8+ T cells in chronic HIV infection to form immunological synapses

Immune mobilising T cell receptors redirect polyclonal CD8+ T cells in chronic HIV infection to form immunological synapses

Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model

Dynamic Expressions of TIGIT on Splenic T Cells and TIGIT-Mediated Splenic T Cell Dysfunction of Mice With Chronic Toxoplasma gondii Infection

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