CD8-positive memory T cells in tumor-draining lymph nodes of patients with breast cancer

Abstract Background Human immunological memory is a hallmark of the adaptive immune system and plays an important role in the development of effective immune responses against tumors. In the present study, we aimed to determine the frequencies of CD8 + memory T cell subsets including stem memory T cells (TSCM) in tumor-draining lymph nodes of patients with breast cancer (BC).Methods Mononuclear cells were obtained from axillary lymph nodes of 52 untreated patients with BC and stained for CD8, CCR7, CD45RO, CD95 markers to detect different subtypes of memory cells in the CD8 + lymphocyte population. Data were acquired with four-color flow cytometry and analyzed with CellQuest Pro software.Results We observed that 47.65±2.66 of CD8+ lymphocytes expressed the CD45RO marker for memory T cells. Statistical analysis showed that the total frequency of central memory T cells (TCM) and their subset with low CD45RO expression was significantly higher in tumor-involved nodes compared to tumor-free ones (P=0.024 and P=0.017, respectively). Mean CD96 expression (based on mean fluorescence intensity) on the surface of TCM, their CD45RO hi TCM and CD45RO low subsets, and TSCM was higher in patients with stage II compared to those with stage I disease (P<0.05). The percentage of naive CD8 + T cells was significantly higher in tumor-involved lymph nodes compared to tumor-free ones (P=0.025).Conclusions Our data collectively indicate no significant differences in the frequencies of CD8 + lymphocytes or their memory T cell subsets in tumor-draining lymph nodes of patients with BC. However, the frequency of CD45 low TCM along with naive CD8 + lymphocytes was higher in tumor-involved nodes, which suggests that after long-term exposure to the antigen, and despite the immune reaction in order to provide a pool of effective memory cells, memory cell differentiation is blocked in early-stage (CD45RO low ) due to tumor-derived suppressive factors. Identifying the molecular and cellular mechanisms behind this suppression can provide invaluable tools for adoptive T cell therapies in cancer.

Download Full-text

CD8-positive memory T cells in tumor-draining lymph nodes of patients with breast cancer

10.21203/rs.2.13183/v3 ◽

2020 ◽

Author(s):

Yasmin Vahidi ◽

Mandana Bagheri ◽

Abbas Ghaderi ◽

Zahra Faghih

Keyword(s):

Breast Cancer ◽

T Cells ◽

T Cell ◽

Lymph Nodes ◽

Memory T Cells ◽

T Cell Subsets ◽

Axillary Lymph ◽

Memory Cells ◽

Color Flow ◽

Draining Lymph Nodes

Abstract Background: Human immunological memory is a hallmark of the adaptive immune system and plays an important role in the development of effective immune responses against tumors. In the present study, we aimed to determine the frequencies of CD8+ memory T cell subsets including stem memory T cells (TSCM) in tumor-draining lymph nodes of patients with breast cancer (BC). Methods: Mononuclear cells were obtained from axillary lymph nodes of 52 untreated patients with BC and stained for CD8, CCR7, CD45RO, CD95 markers to detect different subtypes of memory cells in the CD8+ lymphocyte population. Data were acquired on four-color flow cytometer and analyzed with CellQuest Pro software. Results: We observed that 47.65±2.66% of CD8+ lymphocytes expressed the CD45RO, a marker for memory T cells. Statistical analysis showed that the total frequency of central memory T cells (TCM) and their subset with low CD45RO expression was significantly higher in tumor-involved nodes compared to tumor-free ones (P=0.024 and P=0.017, respectively). The level of CD95 expression (based on mean fluorescence intensity) on the surface of TCM, their CD45ROhi and CD45ROlow subsets, and TSCM was higher in patients with stage II compared to those in stage I (P<0.05). In addition, the percentage of naive CD8+ T cells was significantly lower in tumor-involved lymph nodes compared to tumor-free ones (P=0.025). Conclusions: Our data collectively indicate no significant differences in the frequencies of CD8+ lymphocytes or their memory subsets in tumor-draining lymph nodes of patients with BC. However, the frequency of CD45low TCM was higher in tumor-involved nodes. Along with a decrease in the frequency of naive T cells, the higher frequency of CD45low TCM suggests that despite the immune reaction to provide a pool of effective memory cells, it is blocked in early-stage of memory cells’ differentiation (CD45ROlow), probably by tumor-derived suppressive factors. Identifying the molecular and cellular mechanisms behind this suppression can provide invaluable tools for adoptive T cell therapies in cancer.

Download Full-text

CD8-positive memory T cells in tumor-draining lymph nodes of patients with breast cancer

10.21203/rs.2.13183/v4 ◽

2020 ◽

Author(s):

Yasmin Vahidi ◽

Mandana Bagheri ◽

Abbas Ghaderi ◽

Zahra Faghih

Keyword(s):

Breast Cancer ◽

T Cells ◽

T Cell ◽

Lymph Nodes ◽

Memory T Cells ◽

T Cell Subsets ◽

Axillary Lymph ◽

Memory Cells ◽

Color Flow ◽

Draining Lymph Nodes

Abstract Background: Human immunological memory is a hallmark of the adaptive immune system and plays an important role in the development of effective immune responses against tumors. In the present study, we aimed to determine the frequencies of CD8 + memory T cell subsets including stem memory T cells (TSCM) in tumor-draining lymph nodes of patients with breast cancer (BC). Methods: Mononuclear cells were obtained from axillary lymph nodes of 52 untreated patients with BC and stained for CD8, CCR7, CD45RO, CD95 markers to detect different subtypes of memory cells in the CD8 + lymphocyte population. Data were acquired on four-color flow cytometer and analyzed with CellQuest Pro software. Results: We observed that 47.65±2.66% of CD8+ lymphocytes expressed the CD45RO, a marker for memory T cells. Statistical analysis showed that the total frequency of central memory T cells (TCM) and their subset with low CD45RO expression was significantly higher in tumor-involved nodes compared to tumor-free ones (P=0.024 and P=0.017, respectively). The level of CD95 expression (based on mean fluorescence intensity) on the surface of TCM, their CD45RO hi and CD45RO low subsets, and TSCM was higher in patients with stage II compared to those in stage I (P<0.05). In addition, the percentage of naive CD8 + T cells was significantly lower in tumor-involved lymph nodes compared to tumor-free ones (P=0.025). Conclusions: Our data collectively indicate no significant differences in the frequencies of CD8 + lymphocytes or their memory subsets in tumor-draining lymph nodes of patients with BC. However, the frequency of CD45 low TCM was higher in tumor-involved nodes. Along with a decrease in the frequency of naive T cells, the higher frequency of CD45 low TCM suggests that despite the immune reaction to provide a pool of effective memory cells, it is blocked in early-stage of memory cells’ differentiation (CD45RO low ), probably by tumor-derived suppressive factors. Identifying the molecular and cellular mechanisms behind this suppression can provide invaluable tools for adoptive T cell therapies in cancer.

Download Full-text

CD8-positive memory T cells in tumor-draining lymph nodes of patients with breast cancer

10.21203/rs.2.13183/v2 ◽

2019 ◽

Author(s):

Yasmin Vahidi ◽

Mandana Bagheri ◽

Abbas Ghaderi ◽

Zahra Faghih

Keyword(s):

Breast Cancer ◽

T Cells ◽

T Cell ◽

Lymph Nodes ◽

Memory T Cells ◽

T Cell Subsets ◽

Axillary Lymph ◽

Memory Cells ◽

Color Flow ◽

Draining Lymph Nodes

Abstract Background: Human immunological memory is a hallmark of the adaptive immune system and plays an important role in the development of effective immune responses against tumors. In the present study, we aimed to determine the frequencies of CD8+ memory T cell subsets including stem memory T cells (TSCM) in tumor-draining lymph nodes of patients with breast cancer (BC). Methods: Mononuclear cells were obtained from axillary lymph nodes of 52 untreated patients with BC and stained for CD8, CCR7, CD45RO, CD95 markers to detect different subtypes of memory cells in the CD8+ lymphocyte population. Data were acquired on four-color flow cytometry and analyzed with CellQuest Pro software. Results: We observed that 47.65±2.66 of CD8+ lymphocytes expressed the CD45RO, a marker for memory T cells. Statistical analysis showed that the total frequency of central memory T cells (TCM) and their subset with low CD45RO expression was significantly higher in tumor-involved nodes compared to tumor-free ones (P=0.024 and P=0.017, respectively). The level of CD95 expression (based on mean fluorescence intensity) on the surface of TCM, their CD45ROhi and CD45ROlow subsets, and TSCM was higher in patients with stage II compared to those in stage I (P<0.05). In addition, the percentage of naive CD8+ T cells was significantly higher in tumor-involved lymph nodes compared to tumor-free ones (P=0.025). Conclusions: Our data collectively indicate no significant differences in the frequencies of CD8+ lymphocytes or their memory subsets in tumor-draining lymph nodes of patients with BC. However, the frequencies of CD45low TCM along with naive CD8+ lymphocytes were higher in tumor-involved nodes, which suggests that after long-term exposure to the antigen, and despite the immune reaction in order to provide a pool of effective memory cells, memory cell differentiation is blocked in early-stage (CD45ROlow) due to tumor-derived suppressive factors. Identifying the molecular and cellular mechanisms behind this suppression can provide invaluable tools for adoptive T cell therapies in cancer.

Download Full-text

Memory CD4+ T cell subsets in tumor draining lymph nodes of breast cancer patients: A focus on T stem cell memory cells

Cellular Oncology ◽

10.1007/s13402-017-0352-6 ◽

2017 ◽

Vol 41 (1) ◽

pp. 1-11 ◽

Cited By ~ 10

Author(s):

Yasmin Vahidi ◽

Zahra Faghih ◽

Abdol-Rasoul Talei ◽

Mehrnoosh Doroudchi ◽

Abbas Ghaderi

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

T Cell ◽

Lymph Nodes ◽

Cancer Patients ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Memory Cells ◽

Breast Cancer Patients ◽

Draining Lymph Nodes

Download Full-text

Impact of multiple hits with cognate antigen on memory CD8+ T-cell fate

International Immunology ◽

10.1093/intimm/dxaa039 ◽

2020 ◽

Vol 32 (9) ◽

pp. 571-581 ◽

Cited By ~ 1

Author(s):

Shiki Takamura

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Memory T Cells ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Primary Immune Response ◽

Memory T Cell ◽

Cognate Antigen ◽

Memory Cd8 T Cell

Abstract Antigen-driven activation of CD8+ T cells results in the development of a robust anti-pathogen response and ultimately leads to the establishment of long-lived memory T cells. During the primary response, CD8+ T cells interact multiple times with cognate antigen on distinct types of antigen-presenting cells. The timing, location and context of these antigen encounters significantly impact the differentiation programs initiated in the cells. Moderate re-activation in the periphery promotes the establishment of the tissue-resident memory T cells that serve as sentinels at the portal of pathogen entry. Under some circumstances, moderate re-activation of T cells in the periphery can result in the excessive expansion and accumulation of circulatory memory T cells, a process called memory inflation. In contrast, excessive re-activation stimuli generally impede conventional T-cell differentiation programs and can result in T-cell exhaustion. However, these conditions can also elicit a small population of exhausted T cells with a memory-like signature and self-renewal capability that are capable of responding to immunotherapy, and restoration of functional activity. Although it is clear that antigen re-encounter during the primary immune response has a significant impact on memory T-cell development, we still do not understand the molecular details that drive these fate decisions. Here, we review our understanding of how antigen encounters and re-activation events impact the array of memory CD8+ T-cell subsets subsequently generated. Identification of the molecular programs that drive memory T-cell generation will advance the development of new vaccine strategies that elicit high-quality CD8+ T-cell memory.

Download Full-text

IL-6 Production by Dendritic Cells Is Dispensable for CD8+Memory T-Cell Generation

BioMed Research International ◽

10.1155/2013/126189 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 6

Author(s):

Jean-François Daudelin ◽

Mélissa Mathieu ◽

Salix Boulet ◽

Nathalie Labrecque

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

B Cell ◽

Memory T Cells ◽

T Cell Memory ◽

Memory Cells ◽

Differential Outcome ◽

Memory T Cell ◽

Antigen Presenting

Following activation, naïve CD8+T cells will differentiate into effectors that differ in their ability to survive: some will persist as memory cells while the majority will die by apoptosis. Signals given by antigen-presenting cells (APCs) at the time of priming modulate this differential outcome. We have recently shown that, in opposition to dendritic cell (DC), CD40-activated B-(CD40-B) cell vaccination fails to efficiently produce CD8+memory T cells. Understanding why CD40-B-cell vaccination does not lead to the generation of functional long-lived memory cells is essential to define the signals that should be provided to naïve T cells by APCs. Here we show that CD40-B cells produce very low amount of IL-6 when compared to DCs. However, supplementation with IL-6 during CD40-B-cell vaccination did not improve memory generation. Furthermore, IL-6-deficient DCs maintained the capacity to promote the formation of functional CD8+effectors and memory cells. Our results suggest that in APC vaccination models, IL-6 provided by the APCs is dispensable for proper CD8+T-cell memory generation.

Download Full-text

Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0308054101 ◽

2004 ◽

Vol 101 (15) ◽

pp. 5610-5615 ◽

Cited By ~ 337

Author(s):

K. M. Huster ◽

V. Busch ◽

M. Schiemann ◽

K. Linkemann ◽

K. M. Kerksiek ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Memory T Cells ◽

T Cell Subsets ◽

Memory T Cell ◽

Selective Expression

Download Full-text

Initiation of Antiretroviral Therapy Restores CD4+T Memory Stem Cell Homeostasis in Simian Immunodeficiency Virus-Infected Macaques

Journal of Virology ◽

10.1128/jvi.00492-16 ◽

2016 ◽

Vol 90 (15) ◽

pp. 6699-6708 ◽

Cited By ~ 13

Author(s):

Emily K. Cartwright ◽

David Palesch ◽

Maud Mavigner ◽

Mirko Paiardini ◽

Ann Chahroudi ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

T Cell ◽

Antiretroviral Therapy ◽

Lymph Nodes ◽

Memory T Cells ◽

Effector Memory ◽

Ki 67 ◽

Memory T Cell ◽

Immunodeficiency Virus

ABSTRACTTreatment of human immunodeficiency virus (HIV) infection with antiretroviral therapy (ART) has significantly improved prognosis. Unfortunately, interruption of ART almost invariably results in viral rebound, attributed to a pool of long-lived, latently infected cells. Based on their longevity and proliferative potential, CD4+T memory stem cells (TSCM) have been proposed as an important site of HIV persistence. In a previous study, we found that in simian immunodeficiency virus (SIV)-infected rhesus macaques (RM), CD4+TSCMare preserved in number but show (i) a decrease in the frequency of CCR5+cells, (ii) an expansion of the fraction of proliferating Ki-67+cells, and (iii) high levels of SIV DNA. To understand the impact of ART on both CD4+TSCMhomeostasis and virus persistence, we conducted a longitudinal analysis of these cells in the blood and lymph nodes of 25 SIV-infected RM. We found that ART induced a significant restoration of CD4+CCR5+TSCMboth in blood and in lymph nodes and a reduction in the fraction of proliferating CD4+Ki-67+TSCMin blood (but not lymph nodes). Importantly, we found that the level of SIV DNA in CD4+transitional memory (TTM) and effector memory (TEM) T cells declined ∼100-fold after ART in both blood and lymph nodes, while the level of SIV DNA in CD4+TSCMand central memory T cells (TCM-) did not significantly change. These data suggest that ART is effective at partially restoring CD4+TSCMhomeostasis, and the observed stable level of virus in TSCMsupports the hypothesis that these cells are a critical contributor to SIV persistence.IMPORTANCEUnderstanding the roles of various CD4+T cell memory subsets in immune homeostasis and HIV/SIV persistence during antiretroviral therapy (ART) is critical to effectively treat and cure HIV infection. T memory stem cells (TSCM) are a unique memory T cell subset with enhanced self-renewal capacity and the ability to differentiate into other memory T cell subsets, such as central and transitional memory T cells (TCMand TTM, respectively). CD4+TSCMare disrupted but not depleted during pathogenic SIV infection. We find that ART is partially effective at restoring CD4+TSCMhomeostasis and that SIV DNA harbored within this subset contracts more slowly than virus harbored in shorter-lived subsets, such as TTMand effector memory (TEM). Because of their ability to persist long-term in an individual, understanding the dynamics of virally infected CD4+TSCMduring suppressive ART is important for future therapeutic interventions aimed at modulating immune activation and purging the HIV reservoir.

Download Full-text

Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors

Journal of Experimental Medicine ◽

10.1084/jem.20071855 ◽

2008 ◽

Vol 205 (1) ◽

pp. 53-61 ◽

Cited By ~ 90

Author(s):

Max Löhning ◽

Ahmed N. Hegazy ◽

Daniel D. Pinschewer ◽

Dorothea Busse ◽

Karl S. Lang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Cell ◽

Memory T Cells ◽

Effector T Cells ◽

Memory Cells ◽

T Helper ◽

Cell Therapies ◽

Memory T Cell

Many vaccination strategies and immune cell therapies aim at increasing the numbers of memory T cells reactive to protective antigens. However, the differentiation lineage and therefore the optimal generation conditions of CD4 memory cells remain controversial. Linear and divergent differentiation models have been proposed, suggesting CD4 memory T cell development from naive precursors either with or without an effector-stage intermediate, respectively. Here, we address this question by using newly available techniques for the identification and isolation of effector T cells secreting effector cytokines. In adoptive cell transfers into normal, nonlymphopenic mice, we show that long-lived virus-specific memory T cells can efficiently be generated from purified interferon γ–secreting T helper (Th) type 1 and interleukin (IL)-4– or IL-10–secreting Th2 effectors primed in vitro or in vivo. Importantly, such effector-derived memory T cells were functional in viral challenge infections. They proliferated vigorously, rapidly modulated IL-7 receptor expression, exhibited partial stability and flexibility of their cytokine patterns, and exerted differential effects on virus-induced immunopathology. Thus, cytokine-secreting effectors can evade activation-induced cell death and develop into long-lived functional memory cells. These findings demonstrate the efficiency of linear memory T cell differentiation and encourage the design of vaccines and immune cell therapies based on differentiated effector T cells.

Download Full-text