T Cell-Signaling Network Analysis Reveals Distinct Differences between CD28 and CD2 Costimulation Responses in Various Subsets and in the MAPK Pathway between Resting and Activated Regulatory T Cells

Kalland, Maria Elisabeth; Oberprieler, Nikolaus G.; Vang, Torkel; Taskén, Kjetil; Torgersen, Knut Martin

doi:10.4049/jimmunol.1101804

Cited by 57 publications

(50 citation statements)

References 53 publications

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“…In line with previous studies on CD2 costimulation (40,41), stimulation of gated or FACS-purified CD8 + CD28 2 T cells via CD2 leads to a stronger phosphorylation of S6 ribosomal protein compared with stimulation with CD3 alone (Fig. 7A: n = 10, Fig.…”

Section: Signaling Pathways Triggered By Cd2 Costimulationsupporting

confidence: 74%

“…Although the CD2-CD58 interaction might promote T cell activation by enhancing adhesion, it has been clearly demonstrated that CD2 engagement selectively enhances distinct TCR signaling pathways (40)(41)(42)(43). To our knowledge, our study is the first to investigate the intracellular signaling events induced in CD28 2 CD8 + T cells upon engagement of CD2 by its natural ligand CD58.…”

Section: Cd28mentioning

confidence: 99%

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CD58/CD2 Is the Primary Costimulatory Pathway in Human CD28−CD8+ T Cells

Leitner

Herndler‐Brandstetter

Zlabinger

et al. 2015

The Journal of Immunology

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A substantial proportion of CD8+ T cells in adults lack the expression of the CD28 molecule, and the aging of the immune system is associated with a steady expansion of this T cell subset. CD28−CD8+ T cells are characterized by potent effector functions but impaired responses to antigenic challenge. CD28 acts as the primary T cell costimulatory receptor, but there are numerous additional receptors that can costimulate the activation of T cells. In this study, we have examined such alternative costimulatory pathways regarding their functional role in CD28−CD8+ T cells. Our study showed that most costimulatory molecules have a low capacity to activate CD28-deficient T cells, whereas the engagement of the CD2 molecule by its ligand CD58 clearly costimulated proliferation, cytokine production, and effector function in this T cell subset. CD58 is broadly expressed on APCs including dendritic cells. Blocking CD58 mAb greatly reduced the response of human CD28−CD8+ T cells to allogeneic dendritic cells, as well as to viral Ags. Our results clearly identify the CD58/CD2 axis as the primary costimulatory pathway for CD8 T cells that lack CD28. Moreover, we show that engagement of CD2 amplifies TCR signals in CD28−CD8+ T cells, demonstrating that the CD2–CD58 interaction has a genuine costimulatory effect on this T cell subset. CD2 signals might promote the control of viral infection by CD28−CD8+ T cells, but they might also contribute to the continuous expansion of CD28−CD8+ T cells during chronic stimulation by persistent Ag.

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Section: Signaling Pathways Triggered By Cd2 Costimulationsupporting

confidence: 74%

Section: Cd28mentioning

confidence: 99%

CD58/CD2 Is the Primary Costimulatory Pathway in Human CD28−CD8+ T Cells

Leitner

Herndler‐Brandstetter

Zlabinger

et al. 2015

The Journal of Immunology

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“…As established by others, 9,10 anti-CD3/anti-CD28 mAb stimulation More distal TCR-initiated signals involved in T-cell proliferation include phosphoinositol-3-kinase-g-dependent phosphorylation of AKT and mitogen-activated protein kinasedependent phosphorylation of extracellular signal-regulated kinase (ERK). 11 EPO significantly blunted anti-CD3/anti-CD28-induced phosphorylation of ERK and AKT at 1-5 minutes ( Figure 7, A and B), the latter of which is a crucial intracellular signaling intermediary involved in T-cell proliferation and expansion.…”

Section: Epo Inhibits T-cell Proliferation By Uncoupling Il-2r Signalingmentioning

confidence: 99%

Immunosuppressive Effects of Erythropoietin on Human Alloreactive T Cells

Cravedi¹,

Manrique²,

Hanlon

et al. 2014

Journal of the American Society of Nephrology

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Correction of anemia with erythropoietin (EPO) is associated with improved kidney transplant outcomes. Emerging evidence, predominantly from animal models, indicates that these observations may be erythropoiesis-independent and that EPO exhibits immunosuppressive properties. We examined the effects of EPO on human T-cell alloimmunity by first documenting that CD4 + and CD8 + T cells express EPO receptor (EPO-R) on their surfaces. In mixed lymphocyte reactions, EPO induced a dose-dependent decrease in allogeneic CD4 + T-cell proliferation (EPO 1000 U/ml: 44.6%622.9% of vehicle, P,0.05; 2000 U/ml: 11.1%64% of vehicle, P,0.001) without inducing cell death. The effects required signals transmitted directly through the EPO-R expressed on T cells, resulting in diminished Th1 differentiation without effects on regulatory T-cell induction. Mechanistic studies revealed that EPO prevented IL-2-induced proliferation by uncoupling IL-2 receptor signaling, inhibiting phosphorylation of the intracellular intermediaries AKT and extracellular signal-regulated kinase that are known to mediate T-cell expansion. EPO treatment reduced expansion of human naïve CD4 + T cells after adoptive transfer into NOD scid gc null mouse recipients, verifying the effects in vivo. Although activated T cells expressed CD131, an alternative EPO receptor, addition of a specific CD131 agonist peptide, ARA290, did not alter T-cell proliferation or cytokine production. Our findings link EPO-R signaling on T cells to inhibition of T-cell immunity, providing one mechanism that could explain the observed protective effects of EPO in kidney transplant recipients. The anemia that commonly occurs in kidney transplant recipients has been hypothesized to contribute to chronic allograft injury, in part by limiting oxygen delivery to the tubulointersitium and as a consequence, enabling fibrogenesis. 1 In support of a link between anemia and kidney allograft injury, results of a 2012 randomized controlled study of erythropoietin (EPO) therapy after transplantation showed that targeting hemoglobin values to a normal range of $13 g/dl slowed progression of chronic allograft nephropathy and prolonged graft survival compared with partial correction of anemia. 2 Although the above-cited clinical study and selected studies in rodents indicate correlations between EPO-induced increases in hematocrit and reduced tubulointerstitial damage as well as preserved renal tubular cells and improved kidney function, 3 direct evidence linking EPO-induced erythropoiesis to better transplant outcomes is lacking. In fact, experiments performed in a fully mismatched rat kidney transplant model showed that EPO, but not the correction of anemia by blood transusion, limits chronic allograft injury, 4,5 supporting the conclusion that the transplant-protective effects of EPO do not require an EPO-induced increase in hematocrit. Among potential alternative mechanisms, emerging evidence from animal models suggests that

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“…Thereafter, cells were fixed with prewarmed BD Phosflow fix buffer I (BD Biosciences) and barcoded three-dimensionally with Pacific Blue, Pacific Orange, and Alexa Fluor 488 (Life Technologies) as described earlier (12). The barcoded cells were permeabilized with BD Phosflow perm buffer III (BD Biosciences) and stained for indicated phosphorylation site-specific Abs.…”

Section: Phosphoflow Signaling Analysismentioning

confidence: 99%

CD8+ T Cells That Coexpress RORγt and T-bet Are Functionally Impaired and Expand in Patients with Distal Bile Duct Cancer

Chellappa

Hugenschmidt

Hagness

et al. 2017

The Journal of Immunology

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CD8+ T cells that express retinoic acid–related orphan receptor (ROR)γt (TC17 cells) have been shown to promote procarcinogenic inflammation and contribute to a tolerogenic microenvironment in tumors. We investigated their phenotype and functional properties in relationship to the pathogenesis of human distal bile duct cancer (DBDC). DBDC patients had an elevated level of type 17 immune responses and the frequency of CD8+RORγt+ T cells (TC17 cells) was increased in peripheral blood. The CD8+RORγt+ T cells represented a highly activated subset and produced IL-17A in equal amount as CD4+RORγt+ T cells (TH17 cells). Most CD8+RORγt+ T cells coexpressed T-bet, a lineage transcription factor for TH1 and TC1 development, suggesting that CD8+RORγt+ T cells undergo plasticity toward a TC17/1-like phenotype with coproduction of IL-17A and INF-γ. In comparison with CD8+RORγt− T cells, the CD8+RORγt+ T cells had a higher level of TCR signaling and were terminally differentiated and exhausted. These cells also had impaired ability to re-express perforin after degranulation and reduced cytotoxic immune function. A subset of CD8+RORγt+ T cells expressing a low level of programmed cell death protein 1 and a high level of OX40 were associated with reduced patient survival. In conclusion, CD8+RORγt+ T cells are proinflammatory and functionally impaired and may contribute to the pathogenesis of DBDC.

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T Cell-Signaling Network Analysis Reveals Distinct Differences between CD28 and CD2 Costimulation Responses in Various Subsets and in the MAPK Pathway between Resting and Activated Regulatory T Cells

Cited by 57 publications

References 53 publications

CD58/CD2 Is the Primary Costimulatory Pathway in Human CD28−CD8+ T Cells

CD58/CD2 Is the Primary Costimulatory Pathway in Human CD28−CD8+ T Cells

Immunosuppressive Effects of Erythropoietin on Human Alloreactive T Cells

CD8+ T Cells That Coexpress RORγt and T-bet Are Functionally Impaired and Expand in Patients with Distal Bile Duct Cancer

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