Postthymic Differentiation of CD4 T Lymphocytes: Naive Versus Memory Subsets and Further Specialization among Memory Cells

2015 ◽  
pp. 72-102
Author(s):  
Kevin J. Horgan ◽  
Yoshiya Tanaka ◽  
Stephen Shaw
Keyword(s):  
T Lymphocytes ◽  
Memory Cells

scholarly journals Turnover of naive- and memory-phenotype T cells.

1994 ◽  
Vol 179 (4) ◽  
pp. 1127-1135 ◽  
Author(s):  
D F Tough ◽  
J Sprent
Keyword(s):  
T Cells ◽  
Drinking Water ◽  
T Lymphocytes ◽  
Memory T Cells ◽  
Surgical Approaches ◽  
Surface Markers ◽  
Memory Cells ◽  
Memory Phenotype ◽  
Multiple Phenotypes ◽  
Thymectomized Mice

On the basis of their surface markers, T lymphocytes are divided into subsets of "naive" and "memory cells". We have defined the interrelationship and relative life spans of naive and memory T cells by examining the surface markers on murine T cells incorporating bromodeoxyuridine, a DNA precursor, given in the drinking water. Three findings are reported. First, using a new method we show that the release of newly formed naive T cells from the unmanipulated thymus is very low (confirming the findings of others with surgical approaches). Second, in thymectomized mice, T cells with a naive phenotype remain in interphase for prolonged periods; however, some of these cells divide and retain (or regain) their "naive" markers. Third, most T cells with a memory phenotype divide rapidly, but others remain in interphase for many weeks. Collectively, the data indicate that long-lived T cells have multiple phenotypes and contain a mixture of memory cells, naive (virgin) cells, and memory cells masquerading as naive cells.

The Humanized Anti PD-1 Antibody, CT-011, Increases Specific CD4+ Effector/Memory and Memory T Lymphocytes in Patients with Diffuse Large B Cell Lymphoma (DLBCL) Following Autologous Stem Cell Transplantation (AuSCT).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1216-1216
Author(s):  
Rinat Rotem-Yehudar ◽  
Philippe Armand ◽  
Steve Devine ◽  
Joseph W. Fay ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
B Cell Lymphoma ◽  
Peripheral Tolerance ◽  
Effector Memory ◽  
Memory Cells ◽  
Antibody Treatment ◽  
Effector Memory Cells ◽  
Memory T Lymphocytes ◽  
Memory Lymphocytes

Abstract Abstract 1216 Poster Board I-238 Background: PD-1 (Program Death-1), an immune inhibitory receptor and its ligands PD-L1 and PD-L2, participate in peripheral tolerance and play a key role in immune suppression and evasion mechanisms in cancer and chronic infectious diseases. PD-1 inhibits activation signals and functions as a pro-apoptotic receptor in effector lymphocytes, and consequently regulates the extent and duration of specific adaptive and innate immune responses. CT-011, a humanized antibody, blocks the function of PD-1, resulting in increased activities of T and NK cells in vitro and in enhanced tumor immunity in experimental tumor models. At the molecular level, the antibody enhances PI3K-mediated survival and trafficking signals, attenuates cell death in effector/memory (CD4+CD45RO+) cells, and enhances trafficking in response to Stromal Cell-derived Factor-1 (SDF-1). We hypothesized that CT-011 would enhance effector/memory cells in patients with DLBCL after AuSCT and delay recurrence. Methods: We treated 41 patients (pts) with DLBCL from 30-90 days after AuSCT with CT-011 and now report data on effector/memory and memory lymphocytes in the first 30 pts. CT-011 was given at a dose of 1.5mg/kg for 3 doses, 6 weeks apart. The primary endpoint was to determine the proportion of patients who have not relapsed or died within 18 months following autologous PBSCT, and it is too early for that analysis. Our secondary endpoint was to measure the number of effector /memory and memory lymphocytes before and after treatment, and those data are the subject of this report. Results: Flow cytometry analyses (Table) on pre (baseline: BL) and post-treatment blood samples from the first 30 pts enrolled show elevated levels of specific effector/memory and memory CD4+ T lymphocytes following treatment with CT-011; the median absolute number (ABS) of effector/memory CD4+CD45RO+CD62L-CCR7- cells was increased by +49% from BL (p<0.05) 6 weeks following the first treatment with CT-011, reaching a 2 fold increase in the ABS levels from BL and a 45% increase in the median percentage of the total lymphocyte population (p<0.05) 4 weeks after the third antibody treatment (week 16). The percentage of peripheral memory CD4+ CD62L-CD127+ cells was also increased by 61% from BL (median, p<0.05) on week 16. The observed increase, particularly of the effector/memory CD4+CD45RO+CD62L-CCR7- lymphocytes, a subset directly linked to PD-1 activity and to tumor immune surveillance, likely indicates a specific cellular response to CT-011, since no significant changes were observed for other memory cell subsets including CD4+CD45RO+CD62L+CCR7+cells, CD4+ CD62L+CD127+ cells, CD8+ CD62L-CD127+, CD8+CD62L+CD127+ cells or CD4+CD25+ FOXP3+ suppressor T cells. Overall no changes were observed in the level of total lymphocytes or T cells throughout 16 weeks of follow up from the 1st antibody treatment. Transient reduction of 32% (median, p<0.05) and 25% (median, p<0.05) in the ABS levels of CD3+CD8+ and CD3+CD45RO+, respectively, was observed at week 12, which recovered to baseline or higher levels on week 16. These changes may be explained by trafficking or recycling of CD8+ effector/memory cells from the periphery to target organs. Conclusions: Consistent with its mechanism of action, CT-011 increases the levels of specific CD4+ effector/memory and memory T lymphocytes. This is the first demonstration of safe induction of effector memory and memory lymphocytes, essential components of tumor- immune control, in lymphoma patients following AuSCT. This antibody may have promise for the treatment of lymphoma. Disclosures: Rotem-Yehudar: Cure Tech: Employment. Gordon:Cure Tech: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Differential effects of HIV viral load and CD4 count on proliferation of naive and memory CD4 and CD8 T lymphocytes

Blood ◽  
2011 ◽  
Vol 118 (2) ◽  
pp. 262-270 ◽  
Author(s):  
Sharat Srinivasula ◽  
Richard A. Lempicki ◽  
Joseph W. Adelsberger ◽  
Chiung-Yu Huang ◽  
Joshua Roark ◽  
...  
Keyword(s):  
Viral Load ◽  
T Lymphocytes ◽  
Microbial Translocation ◽  
Effector Memory ◽  
Memory Cells ◽  
Hiv Viral Load ◽  
Cell Counts ◽  
Cd8 T Lymphocytes ◽  
Cd4 Cell

Abstract We previously showed that HIV infection leads to expansion of a rapidly proliferating pool (s1) of CD4 and CD8 T lymphocytes. In the current study, we used in vivo labeling with bromodeoxyuridine to characterize the kinetics of naive, memory, and activated (HLA-DR+/CD38+) subpopulations of CD4 and CD8 T lymphocytes, and to examine the relationship between kinetic parameters and baseline CD4 counts, HIV viral load, potential markers of microbial translocation, and cytokine levels. Activated cells showed the highest proliferation rates, followed by effector and central memory cells, with naive cells showing the lowest rates, for both CD4 and CD8 T cells. HIV viral load correlated with s1 of CD4 and CD8 effector memory cells, as well as CD8 naive cells, whereas CD4 cell counts correlated inversely with naive CD4 s1. Endotoxin levels showed a weak negative association with CD4 but not CD8 s1. INF-γ and TNF-α were associated with s1 for CD4 and CD8 cells, respectively. Thus, HIV is the primary driving force behind the activation and proliferation of most subsets of both CD4 and CD8 T lymphocytes, whereas naive CD4 cell proliferation likely represents a homeostatic response. Microbial translocation does not appear to play an important role in this proliferation.

Abstract MP057: Associations of CD4+ Memory and Naïve T Lymphocytes and Subclinical Atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA)

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Nels C Olson ◽  
Nancy S Jenny ◽  
Sally A Huber ◽  
Richard A Kronmal ◽  
Bruce M Psaty ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
African Americans ◽  
T Lymphocytes ◽  
Subclinical Atherosclerosis ◽  
Chinese Americans ◽  
Agatston Score ◽  
Memory Cells ◽  
Ethnic Study ◽  
European Americans ◽  
H Pylori

Background: Atherosclerosis is a chronic inflammatory disease involving both innate and adaptive immune responses, characterized by the accumulation of T lymphocytes throughout the atherosclerotic plaque. Therefore, we hypothesized that increased CD4+ memory cells and decreased CD4+ naïve cells would be associated with atherosclerosis. To date, no multi-ethnic population-based studies have examined this question. Methods: Peripheral blood memory and naive subpopulations were measured by flow cytometry and defined by the markers CD4+CD45RO+ and CD4+CD45RA+, respectively. Data were analyzed as a proportion of CD4+ cells. Associations were explored with demographic and cardiovascular disease-related variables, and markers of infection, inflammation and subclinical atherosclerosis in a random subset (n=914 participants, composed of European Americans (n=397), Chinese Americans (n=96), African Americans (n=187) and Hispanics (n=234); mean age 66 years) of the Multi-Ethnic Study of Atherosclerosis (MESA). Agatston score, a measure of coronary calcification, was evaluated by cardiac computed tomography (CT) scan; serologies representing past exposure to pathogens were measured in serum by immunoassays. CD4+ cell indices were measured at Exam 4 (2005-2007); cardiovascular disease variables were obtained at the nearest previous exam; some measures, such as serologies, were available only at baseline (2000-2002). Results: Mean levels of circulating naïve, but not memory, CD4+ T cells were higher in woman than men (30.0% and 26.3%, respectively; P<0.0001) and negatively associated with age (P<0.0001). European Americans (EAs) had higher levels of naïve cells compared with African Americans and Hispanics (30.7%, 26.0% and 25.0%, respectively) and lower levels of memory cells compared with the same groups (50.7%, 55.7% and 58.0%, respectively; P<0.05); Chinese Americans were similar to EAs. Adjusting for age, gender and race/ethnicity, CD4+ naïve cells were inversely associated with past exposure to cytomegalovirus (CMV), Hepatitis A and H. Pylori (P<0.001), while memory cells were positively associated with CMV and H. Pylori (P<0.01). Using standardized linear regression models, CD4+ naïve cells were inversely associated with BMI (β= -1.62 ± 0.48), the inflammatory markers C-reactive protein (CRP) (β= -1.21 ± 0.48) and IL-6 (β= -1.79 ± 0.48) and with a positive Agatston score (β= -1.53 ± 0.65) (P<0.05); memory cells were positively associated with these same variables, after adjusting for age, gender and ethnicity. Conclusion: Differences in CD4+ T lymphocytes, including increased populations of memory cells and decreased populations of naïve cells, are associated with atherosclerosis as estimated by Agatston scores. These findings suggest that excess immune activation, as reflected by these differences, may contribute to atherosclerotic calcification.

Decrease in pool of T lymphocytes with surface phenotypes of effector and central memory cells under Influence of TCR transgenic β-chain expression

2013 ◽  
Vol 78 (5) ◽  
pp. 549-559 ◽  
Author(s):  
Yu. Yu. Silaeva ◽  
A. A. Kalinina ◽  
M. S. Vagida ◽  
L. M. Khromykh ◽  
A. V. Deikin ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Central Memory ◽  
Memory Cells ◽  
Central Memory Cells ◽  
Β Chain

scholarly journals CONTENTS OF CD4+ AND CD8+ EFFECTOR MEMORY CELLS AND PROLIFERATIVE ACTIVITY OF T LYMPHOCYTES IN BRONCHIAL ASTHMA

2019 ◽  
Vol 21 (3) ◽  
pp. 503-516
Author(s):  
M. Sh. Barkovskaya ◽  
E. A. Blinova ◽  
L. V. Grishina ◽  
M. I. Leonova ◽  
V. M. Nepomniashchikch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Bronchial Asthma ◽  
Proliferative Activity ◽  
Memory T Cells ◽  
Effector Memory ◽  
Memory Cells ◽  
Healthy Donors ◽  
Effector Memory Cells

Bronchial asthma is a chronic inflammatory disease of the respiratory tract. T-lymphocytes play a key role in pathogenesis of this allergic disease. The reduction in number of naïve T cells and the accumulation of memory T cells in bronchial asthma are accompanied by dysregulation of T lymphocyte function. In present study, we have investigated the contents of different T lymphocyte subpopulations in peripheral blood as well as in resting and PHA-stimulated cultures, along with their proliferative capacity in patients with bronchial asthma and healthy donors. The study included 10 patients with bronchial asthma (age 45.4±11.8 years). One-half of patients was in remission state, the others having been at the stage of clinical exacerbation. The group of donors was formed by healthy individuals matched by gender and age to the patients. Based on expression of cell surface markers CD45R0, CD62L and CD197 (CCR7), the CD4+ and CD8+T lymphocytes were divided into central (Tcm) and effector memory cells (Tem), naïve T lymphocytes (Tnaïve) and terminally differentiated effector cells (Temra) using flow cytometry technique. The proliferative activity of Tcm, Tem and Tnaïve was evaluated in response to PHA as a functional marker of T cells. We have found that the percentage of peripheral CD4+TemCD62L+ and CD8+TemCD62L+ cells in the patients with asthma exacerbation was significantly reduced, if compared to the donors. Following PHA stimulation, these differences in T cell subsets between the groups of patients and donors were not detectable. We performed a correlation analysis between the memory T cell contents and age of the subjects studied. It was shown that the relative amounts of CD4+ and CD8+ memory cells increased with age in asthmatics, but not in healthy donors. Analysis of mitogen-induced proliferation showed that Tcm and Tnaïve cells proliferated more actively than other subpopulations in both groups. Meanwhile, the proliferative activity of CD4+T lymphocytes and subsets of CD8+Tcm, CD4+Tcm and CD4+Tem62L was higher in the group of asthma patients in remission state than in the patients with exacerbating disease, and healthy donors. The revealed increase in the relative number of memory T cells with age suggests that these cells participate in development of bronchial asthma. Proliferative response of the studied subpopulations, which was comparable to the donor values, suggests a functional maintenance of memory T cells and naïve T lymphocytes in bronchial asthma. The increased proliferation of some T-cell subpopulations in asthmatics in remission suggests an activated state of memory T cells. The observed decrease in the number of CD4+TemCD62L+ and CD8+TemCD62L+ in patients with asthma exacerbation may be, by our opinion, associated with an active inflammatory process in the airways.

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