scholarly journals Persistent CAD activity in memory CD8+ T cells supports rRNA synthesis and ribosomal biogenesis required at rechallenge

2021 ◽  
Author(s):  
Michael Claiborne ◽  
Srona Sengupta ◽  
Liang Zhao ◽  
Matthew L Arwood ◽  
Im-Meng Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
De Novo ◽  
Memory T Cells ◽  
Ribosomal Biogenesis ◽  
Recall Response ◽  
Memory Cd8 T Cells ◽  
Pyrimidine Synthesis ◽  
De Novo Pyrimidine Synthesis ◽  
Rate Limiting

Memory CD8+ T cells are characterized by their ability to persist long after the initial antigen encounter and their ability to generate a rapid recall response. Recent studies have identified a role for metabolic reprogramming and mitochondrial function in promoting the longevity of memory T cells. However, detailed mechanisms involved in promoting the rapid recall response are incompletely understood. Here we identify a novel role for the initial and continued activation of the trifunctional rate-limiting enzyme of the de novo pyrimidine synthesis pathway CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) as critical in promoting the rapid recall response of previously-activated CD8+ T cells. CAD is rapidly phosphorylated upon T cell activation in an mTORC1-dependent manner yet remains phosphorylated long after initial activation. Previously-activated CD8+ T cells display continued de novo pyrimidine synthesis in the absence of mitogenic signals and interfering with this pathway diminishes the speed and magnitude of cytokine production upon rechallenge. Inhibition of CAD does not affect cytokine transcript levels, but diminishes available pre-rRNA, the polycistronic rRNA precursor whose synthesis is the rate-limiting step in ribosomal biogenesis. CAD inhibition additionally decreases levels of detectable ribosomal proteins in previously-activated CD8+ T cells. Overexpression of CAD improves both the cytokine response and proliferation of memory T cells. Overall, our studies reveal a novel and critical role for CAD-induced pyrimidine synthesis and ribosomal biogenesis in promoting the rapid recall response characteristic of memory T cells.

scholarly journals Specific niches for lung-resident memory CD8+ T cells at the site of tissue regeneration enable CD69-independent maintenance

2016 ◽  
Vol 213 (13) ◽  
pp. 3057-3073 ◽  
Author(s):  
Shiki Takamura ◽  
Hideki Yagi ◽  
Yoshiyuki Hakata ◽  
Chihiro Motozono ◽  
Sean R. McMaster ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
De Novo ◽  
Memory T Cells ◽  
Tissue Injury ◽  
Effector Memory ◽  
Respiratory Pathogens ◽  
Damage Site ◽  
Memory Cd8 T Cells ◽  
Specific Localization

CD8+ tissue-resident memory T cells (TRM cells) reside permanently in nonlymphoid tissues and provide a first line of protection against invading pathogens. However, the precise localization of CD8+ TRM cells in the lung, which physiologically consists of a markedly scant interstitium compared with other mucosa, remains unclear. In this study, we show that lung CD8+ TRM cells localize predominantly in specific niches created at the site of regeneration after tissue injury, whereas peripheral tissue-circulating CD8+ effector memory T cells (TEM cells) are widely but sparsely distributed in unaffected areas. Although CD69 inhibited sphingosine 1–phosphate receptor 1–mediated egress of CD8+ T cells immediately after their recruitment into lung tissues, such inhibition was not required for the retention of cells in the TRM niches. Furthermore, despite rigid segregation of TEM cells from the TRM niche, prime-pull strategy with cognate antigen enabled the conversion from TEM cells to TRM cells by creating de novo TRM niches. Such damage site–specific localization of CD8+ TRM cells may be important for efficient protection against secondary infections by respiratory pathogens.

scholarly journals Cell Cycle Entry Control in Naïve and Memory CD8+ T Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
David A. Lewis ◽  
Tony Ly
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Cytotoxic T Lymphocytes ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Antigen Recognition ◽  
Cellular Growth ◽  
Activated T Cells ◽  
Memory Cd8 T Cells ◽  
Cell Cycle Entry

CD8+ T cells play important roles in immunity and immuno-oncology. Upon antigen recognition and co-stimulation, naïve CD8+ T cells escape from dormancy to engage in a complex programme of cellular growth, cell cycle entry and differentiation, resulting in rapid proliferation cycles that has the net effect of producing clonally expanded, antigen-specific cytotoxic T lymphocytes (CTLs). A fraction of activated T cells will re-enter dormancy by differentiating into memory T cells, which have essential roles in adaptive immunity. In this review, we discuss the current understanding of cell cycle entry control in CD8+ T cells and crosstalk between these mechanisms and pathways regulating immunological phenotypes.

scholarly journals CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways

2019 ◽  
Vol 216 (12) ◽  
pp. 2748-2762 ◽  
Author(s):  
Alexander N. Wein ◽  
Sean R. McMaster ◽  
Shiki Takamura ◽  
Paul R. Dunbar ◽  
Emily K. Cartwright ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Memory T Cells ◽  
Respiratory Pathogens ◽  
First Line ◽  
Memory Cd8 T Cells ◽  
Effector Functions ◽  
Signaling Axis ◽  
Resident Memory T Cells

Resident memory T cells (TRM cells) are an important first-line defense against respiratory pathogens, but the unique contributions of lung TRM cell populations to protective immunity and the factors that govern their localization to different compartments of the lung are not well understood. Here, we show that airway and interstitial TRM cells have distinct effector functions and that CXCR6 controls the partitioning of TRM cells within the lung by recruiting CD8 TRM cells to the airways. The absence of CXCR6 significantly decreases airway CD8 TRM cells due to altered trafficking of CXCR6−/− cells within the lung, and not decreased survival in the airways. CXCL16, the ligand for CXCR6, is localized primarily at the respiratory epithelium, and mice lacking CXCL16 also had decreased CD8 TRM cells in the airways. Finally, blocking CXCL16 inhibited the steady-state maintenance of airway TRM cells. Thus, the CXCR6/CXCL16 signaling axis controls the localization of TRM cells to different compartments of the lung and maintains airway TRM cells.

Circulating memory CD8 + T cells are limited in forming CD103 + tissue‐resident memory T cells at mucosal sites after reinfection

2020 ◽  
Author(s):  
Felix M. Behr ◽  
Ammarina Beumer‐Chuwonpad ◽  
Natasja A. M. Kragten ◽  
Thomas H. Wesselink ◽  
Regina Stark ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Memory Cd8 T Cells ◽  
Resident Memory T Cells

De novo alloreactive memory CD8+ T cells develop following allogeneic challenge when CNI immunosuppression is delayed

2015 ◽  
Vol 32 (1) ◽  
pp. 23-28
Author(s):  
M. Hart-Matyas ◽  
A.J. Gareau ◽  
G.M. Hirsch ◽  
T.D.G. Lee
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
De Novo ◽  
Memory Cd8 T Cells

Effective Deletion of Anti-Donor Host Memory Effector Cells by Anti-3rd Party Veto CTLs: Implications to Tolerance Induction in Presensitized Bone Marrow Recipients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 44-44 ◽  
Author(s):  
Shlomit Reich-Zeliger ◽  
Esther Bachar-Lustig ◽  
Yair Reisner
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Tolerance Induction ◽  
Annexin V ◽  
Memory Cells ◽  
Spleen Cells ◽  
Memory Cd8 T Cells ◽  
Effector Cells ◽  
Veto Cells

Abstract Recently we demonstrated that veto CTLs enhance engraftment of mismatched T cell depleted BM in recipient mice following reduced intensity conditioning. This desirable tolerance induction can be further enhanced by combining veto CTLs with CD4+CD25+ cells and Rapamycin. While these results are encouraging, they were largely based on models in which the resistant effector T cells mediating the allorejection are naive CTLp. However, considering that many patients undergoing BMT are presensitized by transfusions of different blood products, memory T cells could play an important role in graft rejection and, therefore, their sensitivity to veto cells could be critical to the implementation of the latter cells in BMT. Clearly, memory T cells respond under less stringent conditions to foreign antigens, compared to their naïve counterparts. In particular, they are programmed to be activated promptly, with a reduced requirement for costimulatory signals and therefore they might be more resistant to veto cells. To address this question we used the 2C mouse model, the CD8 T cells of which express a transgenic TCR against H-2d. The CD8 T cells bearing the TCR transgene can be followed by FACS using staining with a clontypic antibody (1B2) against the transgene. In this model, addition of veto CTLs was shown to inhibit expansion of CD8+1B2+ effector cells by induction of apoptosis which can be monitored by annexin V staining. Thus, in a total of 10 experiments the addition of 5% veto cells to 3 day MLR culture of naive 2C effector cells in the presence of H-2d stimulator cells, led to 76%±9% inhibition of expansion. In order to compare the sensitivity of memory cells in the same model, memory cells were established by immunizing 2C transgenic mice with 1x106 irradiated splenocytes from Balb/c donors (H-2d origin). Six weeks later, splenocytes were harvested and after Ficoll separation were shown to be enriched with memory CD8 T cells(CD44+high CD45Rb+ CD62L+, average in 16 different experiments was 73%±11). Upon addition of 5% veto cells to MLR culture of memory 2C spleen cells in the presence of stimulator cells, 78%±7% inhibition of 2C expansion was found. This veto activity was associated with increased apoptosis of allospecific memory CD8 T cells. Thus, in the absence of veto cells the CD8+1B2+ memory cells exhibited a low level of Annexin V (6%±3%) while in the presence of 5% veto cells, a high level of Annexin V (25%±9%) was detected. The deletion of the 2C memory effectors, as previously shown for naive 2C cells, is largely dependent on the presence of Fas-FasL interaction, as indicated by using memory cells from 2C- lpr mice that lack Fas receptor on the cell surface. Upon addition of veto cells to MLR culture with 2C memory spleen cells from lpr mice, only a minor reduction of expansion (5.5%±6% in the presence of 10% veto CTLs) was detected. In conclusion, these results suggest that veto cells can delete memory effector cells as efficiently as exhibited on naive effector cells and by a similar Fas-FasL dependent mechanism. This finding might have significant implications not only for BMT, but also for the treatment of autoimmune diseases in which memory T cells play a major role.

scholarly journals Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Gaëlle Tilly ◽  
Marion Cadoux ◽  
Alexandra Garcia ◽  
Jérémy Morille ◽  
Sandrine Wiertlewski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
De Novo ◽  
Negative Impact ◽  
Adaptive Immune System ◽  
Underlying Mechanism ◽  
High Dimensional ◽  
Memory Cd8 T Cells ◽  
The Impact

Background and ObjectivesInhibition of de novo pyrimidine synthesis in proliferating T and B lymphocytes by teriflunomide, a pharmacological inhibitor of dihydroorotate dehydrogenase (DHODH), has been shown to be an effective therapy to treat patients with MS in placebo-controlled phase 3 trials. Nevertheless, the underlying mechanism contributing to the efficacy of DHODH inhibition has been only partially elucidated. Here, we aimed to determine the impact of teriflunomide on the immune compartment in a longitudinal high-dimensional follow-up of patients with relapse-remitting MS (RRMS) treated with teriflunomide.MethodsHigh-dimensional spectral flow cytometry was used to analyze the phenotype and the function of innate and adaptive immune system of patients with RRMS before and 12 months after teriflunomide treatment. In addition, we assessed the impact of teriflunomide on the migration of memory CD8 T cells in patients with RRMS, and we defined patient immune metabolic profiles.ResultsWe found that 12 months of treatment with teriflunomide in patients with RRMS does not affect the B cell or CD4 T cell compartments, including regulatory TREG follicular helper TFH cell and helper TH cell subsets. In contrast, we observed a specific impact of teriflunomide on the CD8 T cell compartment, which was characterized by decreased homeostatic proliferation and reduced production of TNFα and IFNγ. Furthermore, we showed that DHODH inhibition also had a negative impact on the migratory velocity of memory CD8 T cells in patients with RRMS. Finally, we showed that the susceptibility of memory CD8 T cells to DHODH inhibition was not related to impaired metabolism.DiscussionOverall, these findings demonstrate that the clinical efficacy of teriflunomide results partially in the specific susceptibility of memory CD8 T cells to DHODH inhibition in patients with RRMS and strengthens active roles for these T cells in the pathophysiological process of MS.

Bone Marrow Memory CD8 T Cells Positively Influence Hematopoietic Stem Cell Function

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3692-3692
Author(s):  
Sulima Geerman ◽  
Fernanda M Pascutti ◽  
Sudeep Bhushal ◽  
Martijn A. Nolte
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Positive Impact ◽  
Acute Infection ◽  
Activated T Cells ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Memory Cd8 T Cells

Abstract The bone marrow (BM) not only serves as a primary, but also as a secondary lymphoid organ, since it can mediate primary T cell responses against blood-borne antigens and it harbors a significant portion of the memory T cell compartment. Yet, it remains unclear to what extent BM T cells affect the local hematopoietic process. This is important from a clinical perspective, since the development of BM failure and anemia is frequently associated with (chronic) T cell-mediated inflammatory diseases, such as rheumatoid arthritis and viral infections. We postulate that particularly hematopoietic stem cells (HSCs) may be susceptible to T cell activity, since HSCs are localized in endothelial BM niches and are thus in close vicinity of where T cells enter the BM parenchyma and get activated. In support of this, we have previously shown that IFNγ, one of the key cytokines produced by activated T cells, strongly impairs HSC self-renewal and enhances their differentiation towards monoctyes, at the expense of neutrophils and erythrocytes. To examine the impact of T cells on HSC function, we performed co-culture assays and found that T cells from murine BM actually have a positive impact on HSC function, as they enhance both their differentiation and self-renewal capacity. This feature is restricted to a subset of memory CD8 T cells in the BM, since neither naïve T cells from BM nor memory CD8 T cells from the spleen showed the same effect. Correspondingly, transgenic mice with only naïve and no memory T cells have fewer HSC numbers than control mice, which can be transiently restored when memory CD8 BM T cells are injected. To test the relevance of these findings in an inflammatory setting, we infected mice with the Armstrong-strain of lymphocytic choriomeningitis virus (LCMV), which induces an acute infection that leads to a strong influx of antigen-experienced T cells in the BM. We found that LCMV-specific memory CD8 T cells isolated from BM 12 days after infection increased both the differentiation and self-renewal capacity of HSCs. Interestingly, HSCs isolated from infected mice also displayed an enhanced propensity to differentiate towards myeloid cells compared to HSCs from non-infected control mice, whereas their self-renewal capacity was not altered. To test whether chronically stimulated T cells are also able to influence HSC function, we infected mice with LCMV clone 13, which leads to a chronic infection and induces exhaustion of the virus-specific T cells. Interestingly, virus-specific T cells isolated from BM 27 days after infection, which were exhausted based on phenotype and function, did not influence HSC differentiation but they were still able to enhance the self-renewal of HSCs from non-infected control mice, although to a lesser extent than in the acute infection. These data illustrate that antigen-experienced memory CD8 T cells in BM have a positive impact on the function of HSCs. Although cytokines produced by activated T cells, such as IFNγ and TNFα, can dramatically impair HSC maintenance, it is intriguing that memory T cells can actually fulfill a positive function on the HSC compartment. We speculate that homing of memory T cells to the BM after viral infection may play an important role in restoring the damage on the hematopoietic compartment that is inflicted by the infection itself and the ensuing cytokine storm. Enhancement of such a positive feedback mechanism may be a promising new strategy for treatment of patients with BM failure. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Route of Immunization with Peptide-pulsed Dendritic Cells Controls the Distribution of Memory and Effector T Cells in Lymphoid Tissues and Determines the Pattern of Regional Tumor Control

2003 ◽  
Vol 198 (7) ◽  
pp. 1023-1034 ◽  
Author(s):  
David W. Mullins ◽  
Stacey L. Sheasley ◽  
Rebecca M. Ream ◽  
Timothy N.J. Bullock ◽  
Yang-Xin Fu ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Lung Metastases ◽  
Memory Cell ◽  
Lung Tumors ◽  
Tumor Control ◽  
Lymphoid Tissues ◽  
Memory Cd8 T Cells ◽  
And Control

We have established that the route of immunization with peptide-pulsed, activated DC leads to memory CD8+ T cells with distinct distributions in lymphoid tissues, which determines the ability to control tumors growing in different body sites. Both intravenous (i.v.) and subcutaneous (s.c.) immunization induced memory T cells in spleen and control of metastatic-like lung tumors. s.c. immunization also induced memory T cells in lymph nodes (LNs), imparting protection against subcutaneously growing tumors. In contrast, i.v. immunization-induced memory was restricted to spleen and failed to impart protective immunity against subcutaneously growing tumors. Memory cell distribution and tumor control were both linked to injection route–dependent localization of DCs in lymphoid compartments. Using peripheral LN–ablated mice, these LNs were shown to be essential for control of subcutaneously growing tumors but not lung metastases; in contrast, using immunized asplenic mice, we found that the spleen is necessary and sufficient for control of lung tumors, but unnecessary for control of subcutaneously growing tumors. These data demonstrate the existence of a previously undescribed population of splenic-resident memory CD8 T cells that are essential for the control of lung metastases. Thus, regional immunity based on memory T cell residence patterns is an important factor in DC-based tumor immunotherapy.

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