CD160-Associated CD8 T-Cell Functional Impairment Is Independent of PD-1 Expression

Viganó, Selena; Banga, Riddhima; Bellanger, Florence; Pellaton, Céline; Farina, A.; Comte, Denis; Harari, Alexandre; Perreau, Matthieu

doi:10.1371/journal.ppat.1004380

Cited by 66 publications

(59 citation statements)

References 43 publications

(73 reference statements)

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“…Therefore, we analyzed the expression of two additional inhibitory molecules which are suggested to play a role in T cell regulation, i.e., CD160 and 2B4. CD160 competes with BTLA for binding to herpes virus entry mediator (HVEM) and has been shown to negatively regulate TCR-mediated signaling [26]. Crosslinking of 2B4 on T cells decreases proliferation, and 2B4 expression is upregulated on exhausted T cells [27, 28].…”

Section: Resultsmentioning

confidence: 99%

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T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

Zelle‐Rieser¹,

Thangavadivel²,

Biedermann³

et al. 2016

J Hematol Oncol

211

214

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BackgroundMultiple myeloma is an incurable plasma cell malignancy that is mostly restricted to the bone marrow. Cancer-induced dysfunction of cytotoxic T cells at the tumor site may be responsible for immune evasion and therapeutical failure of immunotherapies. Therefore, enhanced knowledge about the actual status of T cells in myeloma bone marrow is urgently needed. Here, we assessed the expression of inhibitory molecules PD-1, CTLA-4, 2B4, CD160, senescence marker CD57, and CD28 on T cells of naive and treated myeloma patients in the bone marrow and peripheral blood and collected data on T cell subset distribution in both compartments. In addition, T cell function concerning proliferation and expression of T-bet, IL-2, IFNγ, and CD107a was investigated after in vitro stimulation by CD3/CD28. Finally, data was compared to healthy, age-matched donor T cells from both compartments.MethodsMulticolor flow cytometry was utilized for the analyses of surface molecules, intracellular staining of cytokines was also performed by flow cytometry, and proliferation was assessed by 3H-thymidine incorporation. Statistical analyses were performed utilizing unpaired T test and Mann-Whitney U test.ResultsWe observed enhanced T cell exhaustion and senescence especially at the tumor site. CD8+ T cells expressed several molecules associated with T cell exhaustion (PD-1, CTLA-4, 2B4, CD160) and T cell senescence (CD57, lack of CD28). This phenotype was associated with lower proliferative capacity and impaired function. Despite a high expression of the transcription factor T-bet, CD8+ T cells from the tumor site failed to produce IFNγ after CD3/CD28 in vitro restimulation and displayed a reduced ability to degranulate in response to T cell stimuli. Notably, the percentage of senescent CD57+CD28− CD8+ T cells was significantly lower in treated myeloma patients when compared to untreated patients.ConclusionsT cells from the bone marrow of myeloma patients were more severely impaired than peripheral T cells. While our data suggest that terminally differentiated cells are preferentially deleted by therapy, immune-checkpoint molecules were still present on T cells supporting the potential of checkpoint inhibitors to reactivate T cells in myeloma patients in combination therapies. However, additional avenues to restore anti-myeloma T cell responses are urgently needed.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0345-3) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

“…However, investigations in multiple myeloma are still pending. CD160, one of the five ligands of herpes virus entrance mediator (HVEM) has the potential to shift immune response towards exhaustion, and its expression has been shown to be independent of PD-1 [26]. Moreover, CD160 blockade has not been investigated in myeloma so far.…”

Section: Discussionmentioning

confidence: 99%

T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

Zelle‐Rieser¹,

Thangavadivel²,

Biedermann³

et al. 2016

J Hematol Oncol

211

214

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“…CD160-HVEM induces robust NK cell effector activity but only in conjunction with cytokines (IFN-β or IL-2) or direct target cell contact, thus acting as a costimulatory signal in NK cells in the context of inflammation (Sedy et al, 2013). However, other studies implicate CD160 in controlling T cell exhaustion (Vigano et al, 2014), results that demand the need for further understanding of the mechanism of action of CD160.…”

Section: Network Wiring In the Tnf Superfamilymentioning

confidence: 99%

“…In NK cells from wild-type animals, CD160 activation required HVEM. However, while CD160 appears to function as an activating receptor in innate NK cells, the function of CD160 in adaptive T cells may be to further limit both CD4 + and CD8 + T cell activation in concert with BTLA and other immune checkpoint inhibitors during HIV or other viral infections (Cai et al, 2008a; El-Far et al, 2014; Peretz et al, 2012; Sedy et al, 2014; Vigano et al, 2014). Thus, CD160 appears to function in a cell-specific manner, and the outcome of therapeutics targeting this receptor likely will depend on the cellular context.…”

Section: Network Wiring In the Tnf Superfamilymentioning

confidence: 99%

The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses

et al. 2016

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Summary Cytokines related to Tumor Necrosis Factor (TNF) provide a communication network essential for coordinating multiple cell types into an effective host defense system against pathogens and malignant cells. The pathways controlled by the TNF superfamily differentiate both innate and adaptive immune cells as well as modulate stromal cells into microenvironments conducive to host defenses. Receptors in the TNFSF family activate diverse cellular functions, from production of type 1 interferons to the modulation of survival of antigen-activated T cells. Here, we focus attention on the subset of TNF superfamily receptors encoded on the immune response locus at Chr 1p36. Recent studies reveal diverse mechanisms utilized by these receptors to either co-stimulate or restrict immune responses. Translation of the fundamental mechanisms of the TNF superfamily is leading to the design of therapeutics that can alter pathogenic processes in several autoimmune diseases or promote immunity to tumors.

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“…In addition, these cells accumulate cell surface markers associated with immune dysfunction, e.g. , inhibitory receptors such as PD-1, CD160, 2B4, TIM-3, and LAG-367891011121314. This pattern persists even after years of successful antiretroviral treatment (ART)910.…”

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confidence: 99%

Perturbed CD8+ T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals

Tauriainen

Scharf

Frederiksen

et al. 2017

Sci Rep

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HIV-specific CD8+ T cells demonstrate an exhausted phenotype associated with increased expression of inhibitory receptors, decreased functional capacity, and a skewed transcriptional profile, which are only partially restored by antiretroviral treatment (ART). Expression levels of the inhibitory receptor, T cell immunoglobulin and ITIM domain (TIGIT), the co-stimulatory receptor CD226 and their ligand PVR are altered in viral infections and cancer. However, the extent to which the TIGIT/CD226/PVR-axis is affected by HIV-infection has not been characterized. Here, we report that TIGIT expression increased over time despite early initiation of ART. HIV-specific CD8+ T cells were almost exclusively TIGIT+, had an inverse expression of the transcription factors T-bet and Eomes and co-expressed PD-1, CD160 and 2B4. HIV-specific TIGIThi cells were negatively correlated with polyfunctionality and displayed a diminished expression of CD226. Furthermore, expression of PVR was increased on CD4+ T cells, especially T follicular helper (Tfh) cells, in HIV-infected lymph nodes. These results depict a skewing of the TIGIT/CD226 axis from CD226 co-stimulation towards TIGIT-mediated inhibition of CD8+ T cells, despite early ART. These findings highlight the importance of the TIGIT/CD226/PVR axis as an immune checkpoint barrier that could hinder future “cure” strategies requiring potent HIV-specific CD8+ T cells.

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CD160-Associated CD8 T-Cell Functional Impairment Is Independent of PD-1 Expression

Cited by 66 publications

References 43 publications

T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses

Perturbed CD8+ T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals

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