Reconstitution of the peripheral immune repertoire following withdrawal of fingolimod

2017 ◽  
Vol 23 (9) ◽  
pp. 1225-1232 ◽  
Author(s):  
Mahtab Ghadiri ◽  
Leslie Fitz-Gerald ◽  
Ayman Rezk ◽  
Rui Li ◽  
Mukanthu Nyirenda ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Laboratory ◽  
Alternative Therapies ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Immune Repertoire ◽  
Drug Induced ◽  
Memory T Cell ◽  
Cell Counts ◽  
Pre Treatment

Background: Following fingolimod cessation, immune reconstitution or lack thereof may have consequences for disease rebound or safety of commencing alternative therapies. Objective: To examine the degree and profile of peripheral blood lymphocyte reconstitution following fingolimod withdrawal. Methods: Total lymphocyte counts (TLC) and CD4+/CD8+ T-cell counts were measured in 18 multiple sclerosis (MS) patients pre-treatment, on fingolimod, and up to 8–9 months post-cessation. T-cell subsets were analyzed using flow cytometry. Results: At 2-week post-fingolimod cessation, TLC reconstitution was variable and not correlated with age, treatment duration, pre-, or on-treatment TLC. Despite normalization of TLC and CD4+:CD8+ ratios over months, naive subsets remained lower and effector memory subsets higher in frequency compared with pre-treatment. Drug-induced increases in ratios of regulatory to pathogenic Th17-containing central memory populations appeared to rapidly return to baseline. Conclusion: Early peripheral lymphocyte reconstitution after fingolimod withdrawal remains partial and heterogeneous. Relative frequencies of circulating naive and memory T-cell subsets may not recover for many months, even when clinical laboratory tests have normalized. Analyzing specific components of the peripheral immune repertoire helps define the overall immune status of patients. To be determined is whether assessment of such immune measures will have implications for the timing and safety of commencing alternative therapies.

scholarly journals The Repertoires of Circulating Human CD8+ Central and Effector Memory T Cell Subsets Are Largely Distinct

Immunity ◽  
2003 ◽  
Vol 18 (2) ◽  
pp. 193-204 ◽  
Author(s):  
Véronique Baron ◽  
Cécile Bouneaud ◽  
Ana Cumano ◽  
Annick Lim ◽  
T.Petteri Arstila ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Memory T Cell

Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4260-4266 ◽  
Author(s):  
Jens Geginat ◽  
Antonio Lanzavecchia ◽  
Federica Sallusto
Keyword(s):  
T Cell ◽  
Receptor Expression ◽  
T Cell Subsets ◽  
Brdu Incorporation ◽  
Effector Memory ◽  
Differentiation Potential ◽  
Memory T Cell ◽  
Proliferation And Differentiation ◽  
Homeostatic Cytokines

Abstract Four human CD8+ T-cell subsets, naive (CCR7+CD45RA+), central memory (TCM, CCR7+CD45RA–), effector memory (TEM, CCR7–CD45RA–), and CD45RA+ effector memory cells (TEMRA, CCR7–CD45RA+) were compared for their capacity to proliferate and differentiate in response to antigen or homeostatic cytokines. Cytokine responsiveness and interleukin-15 receptor expression were low in naive T cells and progressively increased from TCM to TEM and TEMRA. In contrast, the capacity to accumulate in response to T-cell receptor (TCR) or cytokine stimulation showed a reciprocal pattern and was associated with resistance to cell death and Bcl-2 expression. Whereas all TCR-stimulated cells acquired a CD45RA–CCR7– phenotype, cytokine-stimulated cells maintained their phenotype with the exception of TCM cells, which expressed CCR7, CD45RA, and perforin in various combinations. Single CD8+ TCM cells, but not TEM cells, could be expanded with cytokines, and the obtained clones displayed several distinct phenotypes, suggesting that TCM cells are heterogeneous. Consistently, CCR4 expression in the CD8+ TCM pool discriminated CCR4+ type 2 polarized cells (Tc2) and CCR4–CTL precursors. Finally, ex vivo bromodeoxyuridine (BrdU) incorporation experiments revealed that memory subsets have different in vivo proliferation rates, with CCR4–TCM having the highest turnover and TEMRA the lowest. These results show that human CD8+ memory T-cell subsets have different proliferation and differentiation potentials in vitro and in vivo. Furthermore, they suggest that TEMRA cells are generated from a TCM subset upon homeostatic proliferation in the absence of antigen.

scholarly journals Application of a Standardized Flow Cytometry Panel for Defining and Monitoring the Immunophenotype of CAR-T Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5626-5626
Author(s):  
Irene Scarfò ◽  
Kathleen Gallagher ◽  
Marcela V. Maus ◽  
Rebecca Larson ◽  
Maegan Sheehan ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Unmet Need ◽  
Central Memory ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Memory T Cell ◽  
Car T

Chimeric antigen receptor T-cells (CAR-T) have emerged as an extremely promising therapy for hematological malignancies. The immunophenotype of apheresis material and the CAR-T cell product is known to be predictive of the likelihood of response to treatment of certain malignancies. Central memory and stem cell-like memory T cell phenotypes are associated with a more sustained proliferative response and long-term CAR-T persistence (Fraietta et al, Nature Medicine, 2018). There is an unmet need for standardized methods and reagents to reliably profile the memory phenotype of CAR-Ts to better evaluate product quality, and support improvements in CAR-T manufacturing. The BD Biosciences dried memory T-cell panel contains a pre-validated mixture of 7 antibodies for the identification of naïve, stem cell memory, central memory and effector memory CD4+ and CD8+ T cell subsets. The pre-mixed dried antibody tube offers consistency in staining profiles over time and reduces the risk of operator errors. Additional drop-in antibodies can complement the panel and enable more in-depth evaluation of the T cell phenotype. Here we demonstrate the use of this panel with drop-in markers to monitor changes in expression of PD-1, TIM-3, LAG-3, HLA-DR, CD45RO, and CXCR3 on T cells transduced to express our novel anti-CD37 CAR. Cells were stained at day 0 prior to transduction, day 7, and following resting and re-stimulation, and acquired on a 12 color BD FACS Lyric. The use of a standardized memory T-cell panel will allow us to more accurately evaluate how T-cell phenotype impacts on the efficacy and longevity of response in patients receiving CAR-T therapies. Disclosures Maus: INFO PENDING: Other: INFO PENDING. Bornheimer:BD Biosciences: Employment. Hanley:BD Biosciences: Employment. Frigault:Novartis: Patents & Royalties: Royalty; Arcellx, Celgene, Foundation Medicine, Kite/Gilead, Nkarta, Novartis, and Xenetic: Consultancy.

CXCR3 Is Required for the Efficient Recruitment of Bone Marrow-Resident Memory T Cells to Inflamed Tissues,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3242-3242
Author(s):  
Robbert van der Voort ◽  
Claudia Brandao ◽  
Thomas J. Volman ◽  
Viviènne Verweij ◽  
Klaas van Gisbergen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Central Memory ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Memory T Cell

Abstract Abstract 3242 Although the importance of the bone marrow (BM) in hematopoiesis is well known, its function in adaptive immune responses has only recently been acknowledged. Currently it is known that the BM contains fully functional CD4+ and CD8+ T cells that can engage in both primary and secondary immune responses. Interestingly, most of these T cells belong to the memory T cell lineage, identifying the BM as one of the largest memory T cell reservoirs in the body. Since not much is known about the trafficking of BM T cells, we compared the homing phenotype and function of T cell subsets in the BM, blood, spleen and peripheral lymph nodes (pLN). In addition, we determined the expression of chemokine mRNA and protein levels in the BM and other lymphoid organs. We confirmed that at least 80% of the CD4+ and 60% of the CD8+ BM T cells have a memory phenotype, and that most CD4+ T cells belong to the effector memory lineage, while the CD8+ population predominantly consists of central memory T cells. Most BM T cells expressed the chemokine receptor CXCR3, the adhesion molecules P-selectin glycoprotein ligand 1 and VLA-4, and increased levels of CD44 and LFA-1, as compared to T cells from the spleen. In addition, L-selectin was absent from most CD4+ BM T cells, but present on virtually all CD8+ T cells. Notably, the percentage of CXCR3+ T cells within the effector memory and central memory subsets from BM was higher than within the same subsets from pLN. Furthermore, BM contained significant mRNA levels of the CXCR3 ligands CXCL9, CXCL10 and CXCL11. An in vivo migration assay using a mixture of fluorescent-labeled T cells from CXCR3-deficient mice and control mice indicated however that during homeostasis CXCR3 does not play a major role in BM entry or retention. These data suggest that CXCR3 expressed by memory T cells is rather involved in BM exit, than in BM entry. Indeed, we observed that, as compared to control mice, CXCR3−/− mice contained significantly more CD4+ and CD8+ T cells in their BM. Additional in vitro assays demonstrated that CD4+ and CD8+ BM T cells migrated vigorously in response to CXCL9 and CXCL10, generally released in high concentrations during inflammation. Finally, we demonstrate that CXCR3−/− effector/effector memory T cells, but not wild type T cells, accumulate in the BM of mice infected with lymphocytic choriomeningitis virus. Altogether, these data demonstrate that the BM is a major reservoir of memory T cells that employ CXCR3 to quickly respond to chemotactic signals from inflamed tissues. Disclosures: No relevant conflicts of interest to declare.

3-31-27 Changes of naive and effector/memory T-cell subsets and serum soluble ICAM-1 induced by rIFNβ-1b in MS

1997 ◽  
Vol 150 ◽  
pp. S188-S189
Author(s):  
M. Trojano ◽  
C. Avolio ◽  
M. Ruggieri ◽  
F. Giuliani ◽  
F. De Robertis ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Memory T Cell

scholarly journals c-Cbl expression levels regulate the functional responses of human central and effector memory CD4 T cells

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 652-660 ◽  
Author(s):  
Nicolò C. Brembilla ◽  
Johann Weber ◽  
Donata Rimoldi ◽  
Sylvain Pradervand ◽  
Frédéric Schütz ◽  
...  
Keyword(s):  
T Cell ◽  
Ex Vivo ◽  
Cell Receptor ◽  
Negative Regulator ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Functional Responses ◽  
Tcr Signaling ◽  
Memory T Cell ◽  
Cell Functions

Abstract The biochemical mechanisms controlling the diverse functional outcomes of human central memory (CM) and effector memory (EM) T-cell responses triggered through the T-cell receptor (TCR) remain poorly understood. We implemented reverse phase protein arrays to profile TCR signaling components in human CD8 and CD4 memory T-cell subsets isolated ex vivo. As compared with CD4 CM cells, EM cells express statistically significant increased amounts of SLP-76 and reduced levels of c-Cbl, Syk, Fyn, and LAT. Moreover, in EM cells reduced expression of negative regulator c-Cbl correlates with expression of c-Cbl kinases (Syk and Fyn), PI3K, and LAT. Importantly, consistent with reduced expression of c-Cbl, EM cells display a lower functional threshold than CM cells. Increasing c-Cbl content of EM cells to the same level as that of CM cells using cytosolic transduction, we impaired their proliferation and cytokine production. This regulatory mechanism depends primarily on c-Cbl E3 ubiquitin ligase activity as evidenced by the weaker impact of enzymatically deficient c-Cbl C381A mutant on EM cell functions. Our study reports c-Cbl as a critical regulator of the functional responses of memory T cell subsets and identifies for the first time in humans a mechanism controlling the functional heterogeneity of memory CD4 cells.

scholarly journals Different human resting memory CD4+ T cell subsets show similar low inducibility of latent HIV-1 proviruses

2020 ◽  
Vol 12 (528) ◽  
pp. eaax6795 ◽  
Author(s):  
Kyungyoon J. Kwon ◽  
Andrew E. Timmons ◽  
Srona Sengupta ◽  
Francesco R. Simonetti ◽  
Hao Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Latent Reservoir ◽  
Major Barrier ◽  
Memory T Cell ◽  
Hiv 1

The latent reservoir of HIV-1 in resting CD4+ T cells is a major barrier to cure. It is unclear whether the latent reservoir resides principally in particular subsets of CD4+ T cells, a finding that would have implications for understanding its stability and developing curative therapies. Recent work has shown that proliferation of HIV-1–infected CD4+ T cells is a major factor in the generation and persistence of the latent reservoir and that latently infected T cells that have clonally expanded in vivo can proliferate in vitro without producing virions. In certain CD4+ memory T cell subsets, the provirus may be in a deeper state of latency, allowing the cell to proliferate without producing viral proteins, thus permitting escape from immune clearance. To evaluate this possibility, we used a multiple stimulation viral outgrowth assay to culture resting naïve, central memory (TCM), transitional memory (TTM), and effector memory (TEM) CD4+ T cells from 10 HIV-1–infected individuals on antiretroviral therapy. On average, only 1.7% of intact proviruses across all T cell subsets were induced to transcribe viral genes and release replication-competent virus after stimulation of the cells. We found no consistent enrichment of intact or inducible proviruses in any T cell subset. Furthermore, we observed notable plasticity among the canonical memory T cell subsets after activation in vitro and saw substantial person-to-person variability in the inducibility of infectious virus release. This finding complicates the vision for a targeted approach for HIV-1 cure based on T cell memory subsets.

scholarly journals CD4+ Regulatory and Effector/Memory T Cell Subsets Profile Motor Dysfunction in Parkinson’s Disease

2012 ◽  
Vol 7 (4) ◽  
pp. 927-938 ◽  
Author(s):  
Jessica A. Hutter Saunders ◽  
Katherine A. Estes ◽  
Lisa M. Kosloski ◽  
Heather E. Allen ◽  
Kathryn M. Dempsey ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
T Cell ◽  
Motor Dysfunction ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Memory T Cell
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