scholarly journals IL-12 selectively programs effector pathways that are stably expressed in human CD8+ effector memory T cells in vivo

Blood ◽  
2011 ◽  
Vol 118 (14) ◽  
pp. 3890-3900 ◽  
Author(s):  
Fatema Z. Chowdhury ◽  
Hilario J. Ramos ◽  
Laurie S. Davis ◽  
James Forman ◽  
J. David Farrar
Keyword(s):  
Gene Expression ◽  
Central Memory ◽  
Effector Memory ◽  
Stable Gene ◽  
Memory Cells ◽  
Effector Functions ◽  
Central Memory Cells ◽  
Induced Genes ◽  
Unique Program

Abstract CD8+ cytotoxic T lymphocytes play a major role in defense against intracellular pathogens, and their functions are specified by antigen recognition and innate cytokines. IL-12 and IFN-α/β are potent “signal 3” cytokines that are involved in both effector and memory cell development. Although the majority of effector cells are eliminated as inflammation resolves, some survive within the pool of memory cells and retain immediate effector function. In this study, we demonstrate that IL-12 instructs a unique program of effector cell differentiation that is distinct from IFN-α/β. Moreover, effector memory (TEM) cells within peripheral blood display many common attributes of cells differentiated in vitro in response to IL-12, including proinflammatory cytokine secretion and lytic activity. A pattern of IL-12–induced genes was identified that demarcate TEM from central memory cells, and the ontologies of these genes correlated precisely with their effector functions. Further, we uncovered a unique program of gene expression that was acutely regulated by IL-12 and reflected in stable gene expression patterns within TEM, but not T central memory cells in vivo. Thus, this study directly links a selective set of IL-12–induced genes to the programming of effector functions within the stable population of human CD8+ TEM cells in vivo.

scholarly journals Rapid default transition of CD4 T cell effectors to functional memory cells

2007 ◽  
Vol 204 (9) ◽  
pp. 2199-2211 ◽  
Author(s):  
K. Kai McKinstry ◽  
Susanne Golech ◽  
Won-Ha Lee ◽  
Gail Huston ◽  
Nan-Ping Weng ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cd4 T Cell ◽  
Effector Memory ◽  
Memory Cells ◽  
Two Stages

The majority of highly activated CD4 T cell effectors die after antigen clearance, but a small number revert to a resting state, becoming memory cells with unique functional attributes. It is currently unclear when after antigen clearance effectors return to rest and acquire important memory properties. We follow well-defined cohorts of CD4 T cells through the effector-to-memory transition by analyzing phenotype, important functional properties, and gene expression profiles. We find that the transition from effector to memory is rapid in that effectors rested for only 3 d closely resemble canonical memory cells rested for 60 d or longer in the absence of antigen. This is true for both Th1 and Th2 lineages, and occurs whether CD4 T cell effectors rest in vivo or in vitro, suggesting a default pathway. We find that the effector–memory transition at the level of gene expression occurs in two stages: a rapid loss of expression of a myriad of effector-associated genes, and a more gradual gain of expression of a cohort of genes uniquely associated with memory cells rested for extended periods.

scholarly journals CHARACTERIZATION OF CENTRAL AND EFFECTOR CD4⁺ MEMORY CELLS IN PSORIASIS

2021 ◽  
Vol 23 (4) ◽  
pp. 969-974
Author(s):  
A. V. Kolerova ◽  
D. A. Mikailova ◽  
M. A. Beimanova ◽  
E. A. Blinova
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Central Memory ◽  
Effector Memory ◽  
Memory Cells ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Central Memory Cells ◽  
Effector Memory Cells ◽  
Severity Of The Disease

Psoriasis is a chronic autoimmune disease in which the skin and joints are involved in the pathological process. It was found that the recurrence of rashes in this disease occurs due to the resident memory cells of the skin. The number of CD4+CCR3+ effector memory cells in peripheral blood correlates with the severity of the disease. Therefore, the aim of our work is to study the phenotype of peripheral blood memory cells in patients with psoriasis.The study included 6 healthy donors: average age – 45.4 (min – 29, max – 55), women – 3, men – 3; 10 patients with psoriasis: women – 4, men – 6, average age – 37.3 (min – 23, max – 57), of which 5 patients with PASI > 10 and 5 patients with PASI < 10. The exclusion criteria for the study were the presence of autoimmune, oncological and hematological diseases, systemic therapy with immunosuppressive drugs for 1 month. Patients signed informed consent to participate in the study. Isolation of peripheral blood mononuclear cells was performed in a density gradient of ficoll-urographin (p = 1.082 g/L). Then cells were stained with fluorochrome-conjugated monoclonal antibodies to surface markers of central (Tcm) and effector (Tem) CD4+ memory cells (CD4, CD45RO, CD197), the α-chain of the IL-7 receptor (CD127), and the γ-chain of the IL-7 receptor (CD132). Statistical analysis of the data obtained was performed using the Statistica 6.0 software package.The percent of Tcm in the peripheral blood of donors was 33.4% (in – 18.2, max – 43.7), Tem – 28.7% (min – 13.6, max – 38.9), in patients with psoriasis: Tcm – 28.65% (min – 13.3, max – 59.6), Tem – 21.5% (min – 9.3, max – 38.6). In the peripheral blood of patients with psoriasis, among the central CD4+ memory cells, the proportion of CD127+CD132- -cells is 26.00%, CD127+CD132+ – 1.69%, CD127+CD132- – 69.00%, CD127- CD132+ – 1.94%. Among effector CD4+ memory cells, the proportion of CD127+CD132- -cells is 23.58%, CD127+CD132+ – 1.18%, CD127+CD132- – 69.84%, CD127- CD132+ – 0.70%. A direct correlation was found between the number of CD127- CD132+ central memory cells and the PASI value (r = 0.639, p < 0.05).In patients with psoriasis, the proportion of central memory cells is higher than in healthy donors, while the number of effector memory cells is lower. A direct correlation was found between the number of central cells expressing the γ-chain of the IL-7 receptor and the severity of the disease. Activated memory cells are characterized by high expression of CD132. It can be assumed that this population of memory cells plays a role in maintaining autoimmune inflammation in patients with this disease, and also participates in the repopulation of skin resident memory cells. 

WED 183 Cladribine tablets effects on t cell subsets in patients with early ms

2018 ◽  
Vol 89 (10) ◽  
pp. A25.2-A25
Author(s):  
Olaf Stuve ◽  
Per Soelberg-Sorensen ◽  
Thomas Leist ◽  
Yann Hyvert ◽  
Doris Damian ◽  
...  
Keyword(s):  
T Cell ◽  
Central Memory ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Clinical Effects ◽  
Memory Cells ◽  
Central Memory Cells ◽  
Effector Memory Cells ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

BackgroundBecause of the durable clinical effects of cladribine tablets 3.5 mg/kg (CT3.5) in patients with multiple sclerosis, the influence of treatment on cells with regulatory immune function is of interest.ObjectiveExamine effects on central memory; effector memory; and naturally occurring regulatory (nTregs) CD4 +T cells after first administration of CT3.5 in ORACLE-MS.MethodsPeripheral blood T-lymphocytes were immunophenotyped at baseline, and Weeks 5, 13, 24, 48 in CT3.5 treated patients (n=41). Absolute numbers and proportions of central memory (CD4+RO+CCR7+), effector memory (CD4+RO+CCR7-), Th1-type (CD4+CXCR3+), nTregs (CD4+CD25+CD127-), including naïve-like and memory-like nTregs were measured.ResultsGreatest median reductions in absolute numbers occurred at Week-13 for effector memory cells (−54%); Week-24 for central memory (−63%) and Th1-type cells (−51%); with similar/slightly increased levels at Week-48. There was ~5% reduction in proportion of central memory cells, but no change in proportions of effector memory and Th1-type cells. Absolute numbers of nTregs (−48%), naïve-like (−67%) and memory-like nTregs (−42%) decreased by Week-48. nTregs and naïve-like nTregs proportions were unchanged. Proportions of memory-like nTregs slightly increased up to 48 Weeks.ConclusionCT3.5 administration has a comparable effect on CD4+ T cell subpopulations, with no dramatic shifts in proportions.Disclaimerhttp://medpub-poster.merckgroup.com/ABN2018DISC_ORACLE.pdf

scholarly journals A primary role for human central memory cells in tissue immunosurveillance

2018 ◽  
Vol 2 (3) ◽  
pp. 292-298 ◽  
Author(s):  
Ahmed Gehad ◽  
Jessica E. Teague ◽  
Tiago R. Matos ◽  
Victor Huang ◽  
Chao Yang ◽  
...  
Keyword(s):  
Human Skin ◽  
Central Memory ◽  
Primary Role ◽  
Human Tissues ◽  
Memory Cells ◽  
Effector Functions ◽  
Key Points ◽  
Central Memory Cells

Key Points Human TCM are tissue tropic, have impressive effector functions, and are found in noninflamed human tissues. TCM can act alone to induce inflammation in human skin–grafted mice; results suggest a role for human TCM in primary immunosurveillance.

scholarly journals Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates

2008 ◽  
Vol 118 (1) ◽  
pp. 294-305 ◽  
Author(s):  
Carolina Berger ◽  
Michael C. Jensen ◽  
Peter M. Lansdorp ◽  
Mike Gough ◽  
Carole Elliott ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Central Memory ◽  
T Cell Memory ◽  
Memory Cells ◽  
Cell Memory ◽  
Central Memory Cells

scholarly journals Downregulation of Prdm16 mRNA is a specific antileukemic mechanism during HOXB4-mediated HSC expansion in vivo

Blood ◽  
2014 ◽  
Vol 124 (11) ◽  
pp. 1737-1747 ◽  
Author(s):  
Hui Yu ◽  
Geoffrey Neale ◽  
Hui Zhang ◽  
Han M. Lee ◽  
Zhijun Ma ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stable Gene ◽  
Self Renewal ◽  
Key Points ◽  
Stable Gene Expression

Key Points HOXB4 induces stable gene expression changes in transplanted HSCs that drive balanced self-renewal and differentiation divisions. Marked downregulation of Prdm16 occurs concurrently with HOXB4-mediated HSC expansion and functions to prevent leukemia in vivo.

scholarly journals Subsets of Memory Cytotoxic T Lymphocytes Elicited by Vaccination Influence the Efficiency of Secondary Expansion In Vivo

2004 ◽  
Vol 78 (1) ◽  
pp. 206-215 ◽  
Author(s):  
Michael S. Seaman ◽  
Fred W. Peyerl ◽  
Shawn S. Jackson ◽  
Michelle A. Lifton ◽  
Darci A. Gorgone ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Memory T Cells ◽  
Central Memory ◽  
Effector Memory ◽  
Interleukin 12 ◽  
Effector Cells ◽  
Memory Cytotoxic T Lymphocytes

ABSTRACT Vaccine-elicited cytotoxic T lymphocytes (CTL) should be long-lived memory cells that can rapidly expand in number following re-exposure to antigen. The present studies were initiated to analyze the ability of plasmid interleukin-12 (IL-12) to augment CTL responses in mice when delivered during the peak phase of an immune response elicited by a plasmid human immunodeficiency virus type 1 gp120 DNA vaccine. Delivery of plasmid IL-12 on day 10 postimmunization resulted in a robust expansion of gp120-specific CD8+ T cells, as measured by tetramer, gamma interferon ELISPOT, and functional-killing assays. Interestingly, this delayed administration of plasmid IL-12 had no significant effect on antigen-specific CD4+-T-cell and antibody responses. Phenotypic analyses suggested that administration of plasmid IL-12 near the time of the peak CTL response activated and expanded antigen-specific effector cells, preventing their loss through apoptosis. However, this IL-12-augmented population of gp120-specific CD8+ T cells did not efficiently expand following gp120 boost immunization, suggesting that these effector cells would be of little utility in expanding to contain a viral infection. Analyses of the phenotypic profile and anatomic distribution of the plasmid IL-12-augmented CTL population indicated that these lymphocytes were primarily effector memory rather than central memory T cells. These observations suggest that CTL-based vaccines should elicit central memory rather than effector memory T cells and illustrate the importance of monitoring the phenotype and functionality of vaccine-induced, antigen-specific CTL.

scholarly journals Pomalidomide Induces Expansion of Activated and Central Memory CD4+ and CD8+ T Cells in Vivo in Patients with and without HIV Infection

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4128-4128 ◽  
Author(s):  
Mark N. Polizzotto ◽  
Irini Sereti ◽  
Thomas S. Uldrick ◽  
Kathleen M. Wyvill ◽  
Stig M. R. Jensen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Kaposi Sarcoma ◽  
Central Memory ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Significant Difference

Abstract Background: Despite antiretroviral therapy (ART), people with HIV continue to exhibit immune deficits including failure to fully reconstitute CD4 T cell numbers and function, resulting in increased risks of tumors and infections and reduced response to vaccination. Pomalidomide, a derivative of thalidomide (IMID), has immunomodulatory properties that may be beneficial in this setting. We explored its impact on lymphocyte number and activation in patients with and without HIV treated within a prospective clinical trial for Kaposi sarcoma. Methods: Patients received pomalidomide 5mg orally for 21 days of 28 day cycles. Assessments were performed every 4 weeks for lymphocyte numbers, Kaposi sarcoma associated herpesvirus (KSHV/HHV8) viral load (VL) and HIV VL and at 8 weeks for T cell subsets and activation by immunophenotyping of peripheral blood mononuclear cells (PBMC). KSHV VL in PBMC and HIV VL in plasma were assayed by quantitative PCR; for HIV VL we used an ultrasensitive single copy assay. Changes from baseline were evaluated using the Wilcoxon signed rank test with P<0.005 considered significant given multiple comparisons. Differences in changes between the HIV infected and uninfected groups were evaluated using the Wilcoxon rank sum test. Study registered as NCT1495598. Results: 19 patients (12 HIV infected, 7 uninfected) median age 50 years (range 32-74) were studied. All with HIV were receiving ART for median 48 months (7-227), HIV VL 1.5 copies/mL (<0.5–37), and CD4 378 cells/µl (135–752). At week 4 and 8 of therapy we observed significant increases in CD4 and CD8 counts, with a decline in CD19 B cells and no change in NK cells or HIV VL. A transient increase in KSHV VL was seen at week 4, not sustained at week 8: Abstract 4128. Table 1ParameterBaseline (cells/µl unless noted)Change to Week 4 (Med, range)PChange to Week 8 (Med, range)PCD31143 (525–2305)+264 (-419–1524)0.0028+210 (-496–1455)0.0020CD4429 (135–1171)+107 (-87–650)0.0009+86 (-37–491)0.0015CD8495 (259–1529)+108 (-271–915)0.0085+155 (-495–834)0.0046NK184 (28–557)+30 (-130–117)0.52+2 (-174–127)0.98CD19139 (9–322)-47 (-117–76)0.0039-79 (-169–62)<0.0001KSHV VL 0 copies/PBMC (0–8750)+23 (-92–5250)0.00980 (-92–20850)0.31Plasma HIV VL (infected pts)1.5 copies/mL (<0.5–37)+0.3 (-1.5–3.0)0.75+0.75 (0–28)0.13 In addition, at week 8 both CD4 and CD8 T cells showed significant increases in activation (CD38+, HLADR+ and DR+/38+) and decreases in senescence (CD57+). Both also showed a significant shift towards increased central memory (CM) and away from naive (N) and effector (E) phenotypes, with no change in effector memory (EM) cells: Abstract 4128. Table 2CD4 SubsetsBaseline (%) (med, range)Absolute Change in % at Week 8 (med, range)PRO- 27+ (N)32.6 (13.3–76.5)-6.6 (-35.8–21.6)0.002RO+ 27+ (CM)41.9 (13.6–63.6)+6.4 (-15.5–32.5)0.027RO+ 27- (EM)16.7 (4.6–31.7)+1.7 (-7.2–21.0)0.28RO- 27- (E)3.3 (0.4–14.3)-1.5 (-5.7–0.3)0.000438+34.5 (11.2–67.3)+4.3 (-13.0–19.4)0.024HLA DR+8.9 (3.3–25.0)+8.3 (0.7–19.5)<0.000138+ DR+2.5 (0.6–11.7)+2 (-1.0–8.1)<0.000157+6.3 (0.6–26.6)-1.34 (-16.2–7.6)0.034CD8 SubsetsRO- 27+ (N)21.0 (9.7–70.4)-5.1 (-13.7–14.3)0.019RO+ 27+ (CM)17.1 (2.5–37.9)+8.1 (-8.4–18.6)0.0047RO+ 27- (EM)18.4 (4.6–40.8)+1.0 (-9.4–44.9)0.35RO- 27- (E)31.8 (4.1-63.7)-6.1 (-47.3–22.5)0.0138+33.4 (8.3–66.0)+19.9 (-0.8–40.6)<0.0001HLA DR+19.6 (5.0–46.4)+11.6 (-4.7–32.1)0.000138+ DR+8.0 (0.4–33.3)+8.5 (0.1–22.6)<0.000157+30.8 (2.9–72.9)-11.0 (-28.5–6.1)<0.0001 There were no significant changes in Ki67 or PD-1 expression in either CD4 or CD8 cells. There was no significant difference between HIV infected and uninfected patient groups in the observed effects on any parameter including cell number and phenotype. Conclusions: Pomalidomide induced significant increases in the number of CD4 and CD8 T cells and the proportion of activated and central memory cells and decreased senescence in both HIV infected and uninfected subjects. Effects were not explained by alterations in HIV viremia. The transient early rise in KSHV VL may reflect reactivation of latent infection and enhance immune killing of KSHV infected cells. This analysis sheds light on possible mechanisms of IMID activity in viral-associated tumors. As the first study of immune modulation by IMIDs in vivo in people with HIV it also suggests exploration of IMIDs to augment immune responsiveness in HIV and other immunodeficiencies is warranted. Disclosures Polizzotto: Celgene Corporation: Research Funding. Off Label Use: Pomalidomide for Kaposi sarcoma. Uldrick:Celgene Corporation: Research Funding. Zeldis:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Yarchoan:Celgene Corporation: Research Funding.

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