scholarly journals PD-1 Signaling Has a Critical Role in Maintaining Regulatory T Cell Homeostasis; Implication for Treg Depletion Therapy By PD-1 Blockade

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 848-848 ◽  
Author(s):  
Takeru Asano ◽  
Yuriko Kishi ◽  
Yusuke Meguri ◽  
Takanori Yoshioka ◽  
Miki Iwamoto ◽  
...  
Keyword(s):  
T Cells ◽  
Low Dose ◽  
Annexin V ◽  
Effector Memory ◽  
Wild Type ◽  
Memory Phenotype ◽  
Treg Depletion ◽  
Inhibitory Molecules ◽  
The Impact

Abstract CD4+ Foxp3+ regulatory T cells (Treg) play a central role in the maintenance of immune tolerance. In the setting of allogeneic hematopoietic stem cell transplantation (HSCT), Treg recovery after transplant has been reported as a critical factor to suppress the onset of graft-versus-host disease (GVHD) and stabilize the immune condition. We previously demonstrated that low-dose IL-2 administration preferentially increased Treg in patients with active chronic GVHD and resulted in clinical improvement of the symptoms (NEJM 2011). In the clinical trial, IL-2 induced selective and rapid proliferation of Treg in the first week of therapy but proliferation subsequently returned to baseline levels despite continued daily administration of IL-2 (Sci Trans Med 2013). By detailed analysis of lymphocytes from patients receiving IL-2 therapy, we found that inhibitory molecule Programmed death-1 (PD-1) expression rapidly increased selectively on Treg 2 weeks after starting IL-2, suggesting PD-1 may work to suppress the excessive proliferation of Treg and stabilize homeostasis of this subset during IL-2 therapy (ASH 2014). However, the cellular mechanisms of inhibition of Treg proliferation to maintain Treg homeostasis has not been characterized. To tackle the issue, we here studied the impact and role of PD-1 expression on Treg by using murine IL-2 therapy model. B6 mice were administrated 5x103 IU IL-2 once a day for 14 days and CD4+CD25+Foxp3+ Treg were analyzed comparing with CD4+CD25-Foxp3- conventional CD4 T cells (Tcon) and CD8+ T cells. These subsets were further divided into subpopulations by the expression of CD44 and CD62L. The expressions of pSTAT5, Ki-67, Bcl-2, Fas, PD-1, CTLA-4, LAG3 and TIM-3 in each subset were also examined. As in human, low-dose IL-2 rapidly enhanced PD-1 on Treg, but not other inhibitory molecules including CTLA-4, LAG-3 and TIM-3. Low-dose IL-2 did not affect the expression level of any inhibitory molecules on Tcon and CD8T cells. To clarify the role of PD-1 expression on Treg, we compared PD-1-/- B6 with wild-type B6. PD-1-/- mice were administrated 5x103 IU IL-2 once a day for 28 days. In the first 7 days, IL-2 induced significantly higher levels of pSTAT5 expression in Treg in PD-1-/- cohort than WT cohort (MFI of pSTAT5; mean 4.8 vs 4.0, p<0.01). This resulted in the stronger proliferation and expansion of Treg in PD-1-/- cohort in the first week of IL-2. However, after 7 days, IL-2 expanded PD-1-/- Treg rapidly decreased and returned to baseline level, while IL-2 treated wild type Treg maintained to increase during the 4 weeks. We confirmed this phenomenon by another experimental system using the combination of low-dose IL-2 and anti-PD-1 antibody, and again found that the initial strong proliferation by IL-2 was just temporally and followed by the collapse of Treg homeostasis. To reveal the mechanism of Treg decrease in the absence of PD-1 signal, we assessed Annexin-V+ cells to detect apoptotic cells at day15. IL-2 treated PD-1-/- Treg showed significantly higher level of Annexin-V+ cells than WT Treg (mean 10.5% vs 4.6%, p<0.01). IL-2 treated WT Treg were predominantly CD44high CD62Lhigh central memory phenotype and this phenotype showed increase of PD-1 expression (%PD-1+ cells; mean 44.6% vs 31.7%, vs control, p<0.0001), in contrast, IL-2 treated PD-1-/- Treg showed the accumulation of CD44high CD62Llow effector memory phenotype, which showed high positivity of Annexin-V (mean 15.4% vs 6.4%, p<0.01). These data suggested that PD-1 modulates subset-balance of Treg and inhibits activation-induced-cell death (AICD). We also examined the expression of surface death receptor Fas and intracellular anti-apoptic protein Bcl-2 at day15 to investigate the pathway of apoptosis by lacking of PD-1 signal. IL-2 treated PD-1-/- Treg showed higher increase of Fas expression (mean MFI, 1.5 vs 1.1, p<0.05) and decrease of Bcl-2 expression (mean MFI, 2.6 vs 3.4, p<0.05) than IL-2 treated WT Treg after IL-2 therapy, suggesting that Fas and Bcl-2 might participate in the regulation of apoptosis. In conclusion, our findings indicate that the PD-1 pathway can limit over activation and proliferation of Treg and prevent apoptosis via Fas and Bcl-2 activity during IL-2 therapy. Our finding may implicate the development of Treg depletion therapy by blocking PD-1 signaling. Disclosures No relevant conflicts of interest to declare.

Abstract 001: Sympathetic Innervation Promotes Bone Marrow Homing of Hypertension-specific CD8 + Effector Memory T Cells

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Liang Xiao ◽  
Hana A Itani ◽  
Jason D Foss ◽  
David G Harrison
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Sympathetic Nerves ◽  
Effector Memory ◽  
Quiescent State ◽  
Ang Ii ◽  
Wild Type ◽  
Cell Homing

We have recently identified a critical role of hypertension-specific effector memory T lymphocytes (T EM cells) in the blood pressure elevation and renal dysfunction caused by repeated hypertensive stimuli. Formed during an initial immune challenge, T EM cells reside in the bone marrow (BM) in a quiescent state for prolonged periods, and can be reactivated upon re-exposure to the hypertensive stimulus. Hypertension is associated with increased sympathetic outflow. We therefore hypothesized that sympathetic nerves regulate accumulation and reactivation of hypertension-specific T EM cells in the BM. We performed unilateral superior cervical ganglionectomy (SCGx) in wild-type C57BL/6 mice, causing selectively sympathectomy of the forelimb on the surgical side. After recovery, mice received Ang II infusion for two weeks. To determine the changes of T cells in the BM that were specific to hypertension, 5х10 6 BM cells were isolated from either the SCGx or control limbs, loaded with proliferation marker CFSE, and co-cultured with 0.5х10 6 splenic dendritic cells isolated from another Ang II-infused mouse. We found 30% less CD8 + T cell proliferation in the SCGx BM compared to control side (1.8±0.1 vs. 2.6±0.3х10 4 ), but no difference in CD4 + T cells. To further study the effect of sympathetic nerves on BM T cell homing, 1х10 7 pan T cells were isolated from CD45.2 + wild-type mice after Ang II infusion and adoptively transferred to CD45.1 mice that had previously undergone unilateral SCGx. Flow cytometry indicated that 7 days after transfer, 25% fewer CD8 + T EM cells from the hypertensive donors homed to the SCGx BM compared to the innervated BM (27.8±2.6 vs. 20.8±2.5 per 10 3 total BM cells). This effect was specific for hypertension as homing of OT-I T EM cells, which are responsive to ovalbumin, was not influenced by sympathectomy. Further adoptive transfer studies using mice lacking beta 2 adrenergic receptors (β2AR) indicate that β2AR in the bone marrow niche, rather than T cell β2AR is critical for T EM cell homing. These data define a novel role of sympathetic nerves in regulation of memory T cell trafficking, and this likely contributes to the predisposition to hypertension and end-organ damage for prolonged periods following an initial episode of hypertension.

Abstract 240: A Potential Role of Memory T cells in Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Hana A Itani ◽  
Feng Zhang ◽  
Liang Xiao ◽  
Wei Chen ◽  
David G Harrison
Keyword(s):  
T Cells ◽  
Angiotensin Ii ◽  
Cd8 T Cells ◽  
Low Dose ◽  
Memory T Cells ◽  
Effector Memory ◽  
Ang Ii ◽  
Memory Response ◽  
Cd8 Memory T Cells

Immunological memory is an important component of the adaptive immune response to pathogenic stimuli. Effector memory T cells, which are CD44high CD62Llow, reside in various non-lymphoid tissues and serve as a first line defense against foreign antigens. We have previously shown that T cells are important in hypertension, but the role of memory T cells has not been defined. Thus we hypothesized that CD8+ memory T cells are component of this memory response. To test this hypothesis, mice initially received two weeks of ang II, were allowed to recover for 3 weeks and were then re-infused with low dose of ang II (140 ng/kg/min) that minimally raises blood pressure in naïve mice. This low-dose of ang II increased blood pressure to 137±6 mmHg in mice that had previously received a vehicle infusion, but to 172±12 mmHg in mice that had received ang II. In keeping with a memory T cell response, we found that angiotensin II causes a 5 to 10-fold increase in CD8+ CD62Lhigh/CD44high/CCR7+ central memory cells in the kidney while reducing these effector memory CD8+ T cells in the spleen. CD8+ memory T cells require co-stimulatory signaling between CD70 on macrophages and CD27 on T cells. We found that angiotensin II infusion increased CD70 mRNA in isolated kidney vessels by 5 to 10-fold. Similarly, flow cytometry revealed that angiotensin II increased macrophages expressing CD70 and CD8+ T cells expressing CD27 expression in the kidney. Thus, these studies indicate that repeated exposures to angiotensin II promote an immune memory response of CD8+ T cells and markedly enhance the hypertensive response to this octapeptide. The role of CD27 and CD70 signaling requires additional study but might serve as a therapeutic target.

scholarly journals Role of T cells during the cerebral infection with Trypanosoma brucei

2021 ◽  
Vol 15 (9) ◽  
pp. e0009764
Author(s):  
Gabriela C. Olivera ◽  
Leonie Vetter ◽  
Chiara Tesoriero ◽  
Federico Del Gallo ◽  
Gustav Hedberg ◽  
...  
Keyword(s):  
T Cells ◽  
Trypanosoma Brucei ◽  
Late Stage ◽  
Early Stage ◽  
Brain Parenchyma ◽  
Effector Memory ◽  
Dependent Manner ◽  
Memory Phenotype ◽  
The Brain

The infection by Trypanosoma brucei brucei (T.b.b.), a protozoan parasite, is characterized by an early-systemic stage followed by a late stage in which parasites invade the brain parenchyma in a T cell-dependent manner. Here we found that early after infection effector-memory T cells were predominant among brain T cells, whereas, during the encephalitic stage T cells acquired a tissue resident memory phenotype (TRM) and expressed PD1. Both CD4 and CD8 T cells were independently redundant for the penetration of T.b.b. and other leukocytes into the brain parenchyma. The role of lymphoid cells during the T.b.b. infection was studied by comparing T- and B-cell deficient rag1-/- and WT mice. Early after infection, parasites located in circumventricular organs, brain structures with increased vascular permeability, particularly in the median eminence (ME), paced closed to the sleep-wake regulatory arcuate nucleus of the hypothalamus (Arc). Whereas parasite levels in the ME were higher in rag1-/- than in WT mice, leukocytes were instead reduced. Rag1-/- infected mice showed increased levels of meca32 mRNA coding for a blood /hypothalamus endothelial molecule absent in the blood-brain-barrier (BBB). Both immune and metabolic transcripts were elevated in the ME/Arc of WT and rag1-/- mice early after infection, except for ifng mRNA, which levels were only increased in WT mice. Finally, using a non-invasive sleep-wake cycle assessment method we proposed a putative role of lymphocytes in mediating sleep alterations during the infection with T.b.b. Thus, the majority of T cells in the brain during the early stage of T.b.b. infection expressed an effector-memory phenotype while TRM cells developed in the late stage of infection. T cells and parasites invade the ME/Arc altering the metabolic and inflammatory responses during the early stage of infection and modulating sleep disturbances.

250 SEA-TGT is a nonfucosylated antibody with distinct and amplified effector function activity that leverages the dependencies of anti-TIGIT anti-tumor activity upon Fc? R engagement

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A271-A271
Author(s):  
Alyson Smith ◽  
Weiping Zeng ◽  
William Siegall ◽  
Bryan Grogan ◽  
Jane Haass ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Activation ◽  
Memory T Cells ◽  
Cd8 T Cell ◽  
Wild Type ◽  
Treg Depletion ◽  
The Impact ◽  
Anti Tumor Activity ◽  
Cell Functionality

BackgroundTIGIT is an immunoregulatory receptor expressed on activated and memory T cells, T regulatory cells (Tregs), and NK cells. TIGIT binding to CD155 and CD112 on tumor cells drives an inhibitory signal resulting in decreased T cell functionality. TIGIT targeting has been reported to release these inhibitory signals, drive Treg depletion, augment CD8 T cell generation, and promote anti-tumor responses.MethodsTo evaluate the impact of antibody backbone on anti-TIGIT action three distinct antibodies with differential backbone effector functions, wild type, Fc(gamma)R null (LALA), and Fc(gamma)R enhanced (nonfucosylated, SEA-TGT), were incorporated onto a human anti-TIGIT antibody and assessed. The nonfucosylated SEA-TGT backbone was distinct from the LALA and wild type backbone through increased binding to activating FcyRIIIa receptor while concomitantly decreasing binding to the inhibitory Fc(gamma)RIIb receptor.ResultsIndependent of backbone all TIGIT antibodies blocked ligand binding and restored CD226 signaling. The effector null backbone neither mediated Treg depletion nor naïve or memory CD8 T cell activation. However, the effector enhanced SEA-TGT significantly increased Treg depletion and activation of CD8 T cells over the comparator wild type anti-TIGIT antibody. The enhanced SEA-TGT also induced innate cell activation not seen with the other backbones. These in vitro results translated to curative in vivo anti-tumor activity in multiple syngeneic models as a single agent. Again, the effector null antibody was inactive in all models whereas the effector enhanced SEA-TGT drove curative responses beyond those seen with the standard wild type backbone. Increased activity correlated with a slight decrease in intra-tumoral Tregs and increases in CD8 memory T cells and innate cell activations. Anti-tumor response was associated with generation of long-term, antigen-specific immunity that resulted in complete tumor rejection upon tumor re-challenge.ConclusionsCollectively, these data indicate that modulation of CD8 T cell functionality is not solely through alterations in the TIGIT/CD226 signaling axis and that our nonfucosylated Fc?R enhanced antibody uniquely activates both adaptive and innate arms of the immune system for maximal CD8 T cell responses. They also underscore the anti-tumor therapeutic potential of a nonfucosylated TIGIT targeting antibody (SEA-TGT) as a monotherapy agent and in combination with PD(L)1 agents. We have initiated a phase 1 trial testing the safety and activity of SEA-TGT in patients with advanced solid tumors and select lymphomas (NCT04254107).Trial RegistrationNCT04254107Ethics ApprovalAnimals studies were approved by and conducted in accordance with Seattle Genetics Institutional Care and Use Committee protocol #SGE-029.

scholarly journals The critical role of T cells in glucocorticoid-induced osteoporosis

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Lin Song ◽  
Lijuan Cao ◽  
Rui Liu ◽  
Hui Ma ◽  
Yanan Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Steady State ◽  
Side Effects ◽  
Critical Role ◽  
Wild Type ◽  
Receptor Activator ◽  
Steady State Levels ◽  
Induced Apoptosis

AbstractGlucocorticoids (GC) are widely used clinically, despite the presence of significant side effects, including glucocorticoid-induced osteoporosis (GIOP). While GC are believed to act directly on osteoblasts and osteoclasts to promote osteoporosis, the detailed underlying molecular mechanism of GC-induced osteoporosis is still not fully elucidated. Here, we show that lymphocytes play a pivotal role in regulating GC-induced osteoporosis. We show that GIOP could not be induced in SCID mice that lack T cells, but it could be re-established by adoptive transfer of splenic T cells from wild-type mice. As expected, T cells in the periphery are greatly reduced by GC; instead, they accumulate in the bone marrow where they are protected from GC-induced apoptosis. These bone marrow T cells in GC-treated mice express high steady-state levels of NF-κB receptor activator ligand (RANKL), which promotes the formation and maturation of osteoclasts and induces osteoporosis. Taken together, these findings reveal a critical role for T cells in GIOP.

Potential role of host effector memory CD8+ T cells in marrow rejection after mixed chimerism induction in cynomolgus monkeys

2010 ◽  
Vol 23 (4) ◽  
pp. 194-203 ◽  
Author(s):  
Kiyoshi Setoguchi ◽  
Hidehiro Kishimoto ◽  
Sakiko Kobayashi ◽  
Hiroaki Shimmura ◽  
Hideki Ishida ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Potential Role ◽  
Mixed Chimerism ◽  
Effector Memory ◽  
Memory Cd8 T Cells ◽  
Cynomolgus Monkeys

scholarly journals A reassessment of the role of B7-1 expression in tumor rejection.

1995 ◽  
Vol 182 (5) ◽  
pp. 1415-1421 ◽  
Author(s):  
T C Wu ◽  
A Y Huang ◽  
E M Jaffee ◽  
H I Levitsky ◽  
D M Pardoll
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Tumor Rejection ◽  
Type B ◽  
Wild Type ◽  
Systemic Immunity ◽  
Murine Tumor

Introduction of the B7-1 gene into murine tumor cells can result in rejection of the B7-1 transductants and, in some cases, systemic immunity to subsequent challenge with the nontransduced tumor cells. These effects have been largely attributed to the function of B7-1 as a costimulator in directly activating tumor specific, major histocompatibility class I-restricted CD8+ T cells. We examined the role of B7-1 expression in the direct rejection as well as in the induction of systemic immunity to a nonimmunogenic murine tumor. B-16 melanoma cells with high levels of B7-1 expression did not grow in C57BL/6 recipient mice, while wild-type B-16 cells and cells with low B7-1 expression grew progressively within 21 d. In mixing experiments with B7-1hi and wild-type B-16 cells, tumors grew out in vivo even when a minority of cells were B7-1-. Furthermore, the occasional tumors that grew out after injection of 100% B-16 B7-1hi cells showed markedly decreased B7-1 expression. In vivo antibody depletions showed that NK1.1 and CD8+ T cells, but not CD4+ T cells, were essential for the in vivo rejection of tumors. Animals that rejected B-16 B7-1hi tumors did not develop enhanced systemic immunity against challenge with wild-type B-16 cells. These results suggest that a major role of B7-1 expression by tumors is to mediate direct recognition and killing by natural killer cells. With an intrinsically nonimmunogenic tumor, this direct killing does not lead to enhanced systemic immunity.

Abstract 12: The Role Of Memory Gamma Delta T Cells In Hypertension And Vascular Damage

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Kevin D Comeau ◽  
Pierre Paradis ◽  
Ernesto L Schiffrin
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
Γδ T Cells ◽  
Effector Memory ◽  
Ang Ii ◽  
Mesenteric Lymph Nodes ◽  
Initial Exposure ◽  
Perivascular Adipose Tissue ◽  
Mild Hypertensive

Background: We recently demonstrated that γδ T cells participate in the pathogenesis of hypertension. Evidence also suggests that memory T cells may develop during an initial hypertensive episode, sensitizing mice to develop hypertension to further mild hypertensive challenges. However, whether memory γδ T cells develop and play a role in hypertension remains unknown. Our objective is to determine if memory γδ T cells sensitize mice to develop hypertension in response to a mild hypertensive challenge. Methods: Ten-12-week-old C57BL/6J mice were exposed or not to a hypertensive challenge (490 ng/kg/min angiotensin II (Ang II), SC) for two weeks, followed by a two-week washout period, and then infused with a subpressor dose of Ang II (140 ng/kg/min Ang II, SC) for two weeks. Blood pressure was measured via telemetry and central, effector, and resident memory γδ T cells were profiled by flow cytometry. Results: Mice exposed to the first hypertensive challenge had a higher systolic blood pressure than the sham group at the end of the subpressor hypertensive challenge (149±6 vs. 122±3 mmHg, P <0.001). After 14-days of Ang II infusion, effector memory γδ T cells increased 5.2-fold in the mesenteric artery perivascular adipose tissue (PVAT, 1.25±0.37% vs. 0.24±0.12%, P <0.05), and 1.8-fold in the mesenteric lymph nodes (mLN, 1.49±0.03% vs. 0.82±0.15%, P <0.05) compared to sham treated mice. After repeated Ang II infusion, central memory γδ T cells decreased by 57% in the aortic PVAT (6.79±1.46% vs. 15.69±2.87%, P <0.05), and by 22% in the mLN (0.18±0.01% vs. 0.23±0.01%, P <0.05) compared to control mice. Conclusion: An initial exposure to a hypertensive stimulus sensitizes mice to develop hypertension to a subsequent subpressor hypertensive challenge and results in the development of memory γδ T cells.

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