scholarly journals Follicular Helper T Cells Remodel the Immune Microenvironment of Pancreatic Cancer via Secreting CXCL13 and IL-21

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3678
Author(s):  
Xuan Lin ◽  
Longyun Ye ◽  
Xu Wang ◽  
Zhenyu Liao ◽  
Jia Dong ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
B Cells ◽  
Tumor Microenvironment ◽  
Programmed Cell Death ◽  
Cd8 T Cells ◽  
Helper T Cells ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Programmed Cell Death 1

Immunosuppression is an important factor for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Follicular helper T cells (Tfh cells) play an anti-tumor role in various malignant solid tumors and predict better patient prognosis. In the present study, we aimed to determine the immunosuppressive mechanism associated with Tfh cells and explore a new strategy to improve the tumor microenvironment of PDAC. Flow cytometry was used to detect the infiltration and proportion of Tfh cells in tumor tissues and peripheral blood from patients with PDAC. The spatial correlations of Tfh cells with related immune cells were evaluated using immunofluorescence. The function of Tfh cells was examined using in vitro and in vivo model systems. The high infiltration of Tfh cells predicted better prognosis in patients with PDAC. Tfh cells recruited CD8+ T cells and B cells by secreting C-X-C motif chemokine ligand 13 (CXCL13), and promoted the maturation of B cells into antibody-producing plasma cells by secreting interleukin 21 (IL-21), thereby promoting the formation of an immunoactive tumor microenvironment. The function of Tfh cells was inhibited by the programmed cell death 1 ligand 1 (PD-L1)/programmed cell death 1 (PD-1) signaling pathway in PDAC, which could be reversed using neoadjuvant chemotherapy. Treatment with recombinant CXCL13, IL-21 and Tfh cells alleviated tumor growth and enhanced the infiltration of CD8+ T cells and B cells, as well as B cell maturation in a PDAC mouse model. Our results revealed the important role of Tfh cells in mediating anti-tumor cellular immunity and humoral immunity in PDAC via secreting CXCL13 and IL-21 and determined a novel mechanism of immunosuppression in PDAC.

scholarly journals Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells

2016 ◽  
Vol 4 (10) ◽  
pp. 845-857 ◽  
Author(s):  
Blanca Homet Moreno ◽  
Jesse M. Zaretsky ◽  
Angel Garcia-Diaz ◽  
Jennifer Tsoi ◽  
Giulia Parisi ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cd8 T Cells ◽  
Murine Melanoma ◽  
Programmed Cell Death 1 ◽  
Syngeneic Model

scholarly journals Mice lacking Programmed cell death-1 show a role for CD8+ T cells in long-term immunity against blood-stage malaria

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Joshua M. Horne-Debets ◽  
Deshapriya S. Karunarathne ◽  
Rebecca J. Faleiro ◽  
Chek Meng Poh ◽  
Laurent Renia ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cd8 T Cells ◽  
Blood Stage ◽  
Programmed Cell Death 1 ◽  
Blood Stage Malaria

scholarly journals Intralymphatic GAD-alum Injection Modulates B Cell Response and Induces Follicular Helper T Cells and PD-1+ CD8+ T Cells in Patients With Recent-Onset Type 1 Diabetes

2022 ◽  
Vol 12 ◽  
Author(s):  
Hugo Barcenilla ◽  
Mikael Pihl ◽  
Jeanette Wahlberg ◽  
Johnny Ludvigsson ◽  
Rosaura Casas
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
B Cells ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Helper T Cells ◽  
Follicular Helper T Cells ◽  
Recent Onset ◽  
Follicular Helper

Antigen-specific immunotherapy is an appealing strategy to preserve beta-cell function in type 1 diabetes, although the approach has yet to meet its therapeutic endpoint. Direct administration of autoantigen into lymph nodes has emerged as an alternative administration route that can improve the efficacy of the treatment. In the first open-label clinical trial in humans, injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) into an inguinal lymph node led to the promising preservation of C-peptide in patients with recent-onset type 1 diabetes. The treatment induced a distinct immunomodulatory effect, but the response at the cell level has not been fully characterized. Here we used mass cytometry to profile the immune landscape in peripheral blood mononuclear cells from 12 participants of the study before and after 15 months of treatment. The immunomodulatory effect of the therapy included reduction of naïve and unswitched memory B cells, increase in follicular helper T cells and expansion of PD-1+ CD69+ cells in both CD8+ and double negative T cells. In vitro stimulation with GAD65 only affected effector CD8+ T cells in samples collected before the treatment. However, the recall response to antigen after 15 months included induction of CXCR3+ and CD11c+Tbet+ B cells, PD-1+ follicular helper T cells and exhausted-like CD8+ T cells. This study provides a deeper insight into the immunological changes associated with GAD-alum administration directly into the lymph nodes.

scholarly journals CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuhong Chen ◽  
Mei Yu ◽  
Yongwei Zheng ◽  
Guoping Fu ◽  
Gang Xin ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
T Cell Subsets ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Autoantibody Production ◽  
Tfh Cells ◽  
Follicular Helper

Abstract Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance.

scholarly journals Programmed Cell Death 1 and Helios Distinguish TCR-αβ+ Double-Negative (CD4−CD8−) T Cells That Derive from Self-Reactive CD8 T Cells

2015 ◽  
Vol 194 (9) ◽  
pp. 4207-4214 ◽  
Author(s):  
Noé Rodríguez-Rodríguez ◽  
Sokratis A. Apostolidis ◽  
Pablo Penaloza-MacMaster ◽  
José Manuel Martín Villa ◽  
Dan H. Barouch ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cd8 T Cells ◽  
Double Negative ◽  
Programmed Cell Death 1

scholarly journals Increased frequency of CD4+ and CD8+ follicular helper T cells in human lymph node biopsies during the earliest stages of rheumatoid arthritis

2021 ◽  
Author(s):  
Dornatien C Anang ◽  
Tamara H. Ramwadhdoebe ◽  
Janine Hahnlein ◽  
Bo van Kuijk ◽  
Noortje Smits ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Lymph Node ◽  
B Cells ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
Helper T Cells ◽  
Healthy Controls ◽  
Tfh Cells ◽  
Follicular Helper

Objectives: Follicular helper T cells (Tfh cells) provide key B cell help, and are essential in germinal center (GC) formation and (auto) antibody generation. To gain more insight into their role during the earliest phase of rheumatoid arthritis (RA) we analyzed their frequencies, phenotype and cytokine profile in peripheral blood and lymphoid tissues. Methods: Using flow cytometry, we studied the frequency of Tfh and B cells in peripheral blood and lymph node (LN) needle biopsies. Three donor groups were included and compared: healthy controls (HCs), autoantibody positive individuals at risk for developing RA (RA-risk individuals), and early RA patients. Ex vivo stimulation of lymphocytes with PMA/ionomycin was performed to assess cytokine secretion by Tfh cells. Results: In blood, the frequency of circular Tfh cells (cTfh) did not differ between study groups. In lymphoid tissue, the frequency of Tfh cells correlated strongly with the frequency of CD19+ B cells. Compared to healthy controls, LN samples of RA patients and RA-risk individuals showed more CD19+ B cells and more CD4+CXCR5+ and CD8+CXCR5+ Tfh cells. These Tfh cells from LNs expressed less IL-21 upon ex vivo stimulation. Conclusion: LN tissue of early RA patients as well as part of RA-risk individuals exhibit increased frequencies of Tfh cells correlating with increased numbers of B cells. Interestingly, IL-21 production is already aberrant in the very early at risk phase of the disease. This suggests that Tfh cells may present a novel rationale for therapeutic targeting during the preclinical stage of the disease to prevent further disease progression.

scholarly journals AB0049 IMMUNE DYSFUNCTION IN ANKYLOSING SPONDYLITIS (AS) AND THE POTENTIAL OF TUMOR NECROSIS FACTOR-Α (TNF-α) INHIBITOR ANBAINUO AS AN EFFECTIVE TREATMENT

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1327.2-1327
Author(s):  
M. Yang ◽  
Q. Lv ◽  
Q. Wei ◽  
J. Gu
Keyword(s):  
T Cells ◽  
Ankylosing Spondylitis ◽  
B Cells ◽  
Immune Function ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Cd4 T Cells ◽  
Helper T Cells ◽  
Effector Memory ◽  
Follicular Helper

Background:Studies into ankylosing spondylitis (AS) and its relationship with immune function are controversial, and the correlation between the efficacy of TNF-α inhibitor and changes in immune function is unclear.Objectives:We conducted a prospective study of T-cell and B-cell subset distribution and analyzed lymphocyte function in AS patients to further clarify changes to the immune system caused by AS and to explore resistance that could contribute to relapse after treatment.Methods:A total of 40 immune cells were tested with flow cytometry, and the results of 105 HC (healthy control) subjects, 177 active-stage AS patients, and 23 AS cases before and after 12 weeks of Anbainuo therapy were analyzed.Results:Compared with the HC group, the proportion of immune cells, such as naïve and central memory CD4+T cells, in AS increased (p<0.0001), but effector memory and terminally differentiated CD4+T cells were decreased (p<0.01 and 0.0001, respectively). Naïve, central memory, and effector memory CD8+T cells were increased (p<0.0001, 0.001, and 0.01, respectively), but terminally differentiated CD8+T cells were decreased (p<0.0001). Th1 cells (helper T cells-1), Tfh1 cells (follicular helper T cells-1), Tc1 cells (cytotoxic T cells-1), and Tregs (regulatory T cells) were lower (p<0.01, 0.05, 0.0001, and 0.001, respectively), but Th17 cells, Tfh17 cells, and Tc cells were higher (p<0.001, 0.0001 and 0.001, respectively). The proportions of total B cells and class-switched B cells were increased (p<0.05), but non-switched B cells, plasma cells, memory B cells, and immature Bregs (regulatory B cells) were lower (p<0.01, 0.0001, 0.0001, and 0.0001, respectively). After Anbainuo therapy, the percentage of Tregs and B10 cells (IL-10-producing regulatory B cells) had increased (p<0.01and 0.05, respectively), and the increase in Tregs was positively correlated with the decrease in CRP (C-reactive protein) (r= 0.489, p=0.018).Conclusion:We found that, in terms of both innate and acquired immunity, active-stage AS patients have an immunity imbalance involving multiple types of immune cells, including CD4+T cells, CD8+T cells, Th cells, Tfh cells, Tc cells, Tregs, Bregs, and B cells. Anbainuo can not only help to inhibit disease activity and partial immune function imbalance in AS but can also increase the number of negative regulatory cells in inflammation.References:[1]Long, S., et al., High frequency of circulating follicular helper T cells is correlated with B cell subtypes in patients with ankylosing spondylitis. Exp Ther Med, 2018. 15(5): p. 4578-4586.[2]An, H., et al., The absolute counts of peripheral T lymphocyte subsets in patient with ankylosing spondylitis and the effect of low-dose interleukin-2. Medicine (Baltimore), 2019. 98(15): p. e15094.Acknowledgments:Thanks to Professor Zhinan Yin for his support and assistance with this studyDisclosure of Interests:None declared

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