2B4 (CD244) induced by selective CD28 blockade functionally regulates allograft-specific CD8+ T cell responses

Liu, Danya; Krummey, Scott M.; Badell, I. Raul; Wagener, Maylene E.; Schneeweis, Lumelle A.; Stetsko, Dawn K.; Suchard, Suzanne J.; Nadler, Steven G.; Ford, Mandy L.

doi:10.1084/jem.20130902

Cited by 60 publications

(76 citation statements)

References 40 publications

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“…Moreover, CD160 blockade has not been investigated in myeloma so far. CD28 downregulation and 2B4 upregulation in the presence of CTLA-4 has been shown in a virus-specific T cell model [47]. We here see a similar situation in myeloma bone marrow, i.e., a high proportion of CD8+ T cells which lost CD28 expression and concomitantly gained CTLA-4 expression and upregulated 2B4.…”

Section: Discussionsupporting

confidence: 82%

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

230

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: Discussionsupporting

confidence: 82%

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

230

214

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“…Alternatively, we demonstrated a decrease in the frequency of ICOS + T cells in belatacept treated animals in this study. In a murine model, both CTLA4-Ig and selective CD28 blockade resulted in impaired upregulation of ICOS after alloactivation (34). Therefore, treatment with CD28-B7 costimulation blockade appears to hinder ICOS upregulation and may also explain the lack of efficacy of combined belatacept and ICOS-Ig in this study.…”

Section: Discussionmentioning

confidence: 99%

A Pilot Trial Targeting the ICOS–ICOS-L Pathway in Nonhuman Primate Kidney Transplantation

Anderson

Song

et al. 2015

American Journal of Transplantation

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Costimulation blockade with the B7-CD28 pathway-specific agent belatacept is now used in clinical kidney transplantation, but its efficacy remains imperfect. Numerous alternate costimulatory pathways have been proposed as targets to synergize with belatacept, one of which being the inducible costimulator (ICOS)-ICOS ligand pathway. Combined ICOS-ICOS-L and CD28-B7 blockade has been shown to prevent rejection in mice, but has not been studied in primates. We therefore tested a novel ICOS-Ig human Fc-fusion protein in a nonhuman primate kidney transplant model alone and in combination with belatacept. ICOS-Ig did not prolong rejection-free survival as a monotherapy or in combination with belatacept. In ICOS-Ig alone treated animals, most graft-infiltrating CD4+ and CD8+ T cells expressed ICOS, and ICOS+ T cells were present in peripheral blood to a lesser degree. Adding belatacept reduced the proportion of graft-infiltrating ICOS+ T cells and virtually eliminated their presence in peripheral blood. Graft-infiltrating T cells in belatacept-resistant rejection were primarily CD8+CD28−, but importantly, very few CD8+CD28− T cells expressed ICOS. We conclude that ICOS-Ig, alone or combined with belatacept, does not prolong renal allograft survival in nonhuman primates. This may relate to selective loss of ICOS with CD28 loss.

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“…Where indicated, animals were treated with 100 ug of anti-CD28 domain antibody on days 0, 2, 4, and 6 (38). Mice were monitored for graft survival, and rejection was defined as <10% viable donor tissue remaining.…”

Section: Methodsmentioning

confidence: 99%

Retrogenic ICOS Expression Increases Differentiation of KLRG-1hiCD127loCD8+ T Cells during Listeria Infection and Diminishes Recall Responses

Liu

Burd

Coopersmith

et al. 2016

The Journal of Immunology

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Following T cell encounter with antigen, multiple signals are integrated to collectively induce distinct differentiation programs within antigen-specific CD8+ T cell populations. Several factors contribute to these cell fate decisions including the amount and duration of antigen, exposure to inflammatory cytokines, and degree of ligation of cosignaling molecules. The inducible costimulator (ICOS) is not expressed on resting T cells but is rapidly upregulated upon encounter with antigen. However, the impact of ICOS signaling on programmed differentiation is not well understood. In this study we therefore sought to determine the role of ICOS signaling on CD8+ T cell programmed differentiation. Through the creation of novel ICOS retrogenic antigen-specific TCR transgenic CD8+ T cells, we interrogated the phenotype, functionality, and recall potential of CD8+ T cells that receive early and sustained ICOS signaling during antigen exposure. Our results reveal that these ICOS signals critically impacted cell fate decisions of antigen-specific CD8+ T cells, resulting in increased frequencies of KLRG-1hiCD127lo cells, altered BLIMP-1, T-bet, and eomesodermin expression, and increased cytolytic capacity as compared to empty vector controls. Interestingly, however, ICOS retrogenic CD8+ T cells also preferentially homed to non-lymphoid organs, and exhibited reduced multi-cytokine functionality and reduced ability to mount secondary recall responses upon challenge in vivo. In sum, our results suggest that an altered differentiation program is induced following early and sustained ICOS expression, resulting in the generation of more cytolyticly potent, terminally differentiated effectors that possess limited capacity for recall response.

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2B4 (CD244) induced by selective CD28 blockade functionally regulates allograft-specific CD8+ T cell responses

Abstract: Blockade of CD28 signals results in the up-regulation of 2B4 on primary CD8+ effectors and plays a critical role in controlling antigen-specific CD8+ T cell responses.

Cited by 60 publications

References 40 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

A Pilot Trial Targeting the ICOS–ICOS-L Pathway in Nonhuman Primate Kidney Transplantation

Retrogenic ICOS Expression Increases Differentiation of KLRG-1hiCD127loCD8+ T Cells during Listeria Infection and Diminishes Recall Responses

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