scholarly journals TSLP-activated dendritic cells induce human T follicular helper cell differentiation through OX40-ligand

2017 ◽  
Vol 214 (5) ◽  
pp. 1529-1546 ◽  
Author(s):  
Lucia Pattarini ◽  
Coline Trichot ◽  
Sofia Bogiatzi ◽  
Maximilien Grandclaudon ◽  
Stephan Meller ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Inflammatory Cells ◽  
Memory B Cells ◽  
Th2 Cells ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Ox40 Ligand ◽  
T Follicular Helper Cell ◽  
Humoral Responses

T follicular helper cells (Tfh) are important regulators of humoral responses. Human Tfh polarization pathways have been thus far associated with Th1 and Th17 polarization pathways. How human Tfh cells differentiate in Th2-skewed environments is unknown. We show that thymic stromal lymphopoietin (TSLP)–activated dendritic cells (DCs) promote human Tfh differentiation from naive CD4 T cells. We identified a novel population, distinct from Th2 cells, expressing IL-21 and TNF, suggestive of inflammatory cells. TSLP-induced T cells expressed CXCR5, CXCL13, ICOS, PD1, BCL6, BTLA, and SAP, among other Tfh markers. Functionally, TSLP-DC–polarized T cells induced IgE secretion by memory B cells, and this depended on IL-4Rα. TSLP-activated DCs stimulated circulating memory Tfh cells to produce IL-21 and CXCL13. Mechanistically, TSLP-induced Tfh differentiation depended on OX40-ligand, but not on ICOS-ligand. Our results delineate a pathway of human Tfh differentiation in Th2 environments.

scholarly journals IL-12 receptor β1 deficiency alters in vivo T follicular helper cell response in humans

Blood ◽  
2013 ◽  
Vol 121 (17) ◽  
pp. 3375-3385 ◽  
Author(s):  
Nathalie Schmitt ◽  
Jacinta Bustamante ◽  
Laure Bourdery ◽  
Salah Eddine Bentebibel ◽  
Stephanie Boisson-Dupuis ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Response ◽  
Memory B Cells ◽  
Helper Cell ◽  
Tfh Cells ◽  
Control Subjects ◽  
Follicular Helper ◽  
Key Points ◽  
T Follicular Helper Cell

Key Points IL-12Rβ1–deficient subjects displayed substantially less circulating memory Tfh and memory B cells than control subjects. The IL-12–STAT4 axis is associated with the development and functions of Tfh cells in vivo in humans.

scholarly journals IL-4–producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells

2009 ◽  
Vol 206 (5) ◽  
pp. 1001-1007 ◽  
Author(s):  
Irah L. King ◽  
Markus Mohrs
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Cd4 T Cells ◽  
Helminth Infection ◽  
Th2 Cells ◽  
Mesenteric Lymph Nodes ◽  
Th2 Response ◽  
Tfh Cells ◽  
Follicular Helper

Interleukin (IL)-4 is the quintessential T helper type 2 (Th2) cytokine produced by CD4+ T cells in response to helminth infection. IL-4 not only promotes the differentiation of Th2 cells but is also critical for immunoglobulin (Ig) G1 and IgE isotype-switched antibody responses. Despite the IL-4–mediated link between Th2 cells and B lymphocytes, the location of IL-4–producing T cells in the lymph nodes is currently unclear. Using IL-4 dual reporter mice, we examined the Th2 response and IL-4 production in the draining mesenteric lymph nodes during infection with the enteric nematode Heligmosomoides polygyrus. We show that although IL-4–competent Th2 cells are found throughout the B and T cell areas, IL-4–producing Th2 cells are restricted to the B cell follicles and associate with germinal centers. Consistent with their localization, IL-4 producers express high levels of CXCR5, ICOS, PD-1, IL-21, and BCL-6, a phenotype characteristic of T follicular helper (Tfh) cells. Although IL-4 was dispensable for the generation of Th2 and Tfh cells, its deletion resulted in defective B cell expansion and maturation. Our report reveals the compartmentalization of Th2 priming and IL-4 production in the lymph nodes during infection, and identifies Tfh cells as the dominant source of IL-4 in vivo.

scholarly journals T follicular helper cells differentiate from Th2 cells in response to helminth antigens

2009 ◽  
Vol 206 (5) ◽  
pp. 991-999 ◽  
Author(s):  
Arielle Glatman Zaretsky ◽  
Justin J. Taylor ◽  
Irah L. King ◽  
Fraser A. Marshall ◽  
Markus Mohrs ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Th2 Cells ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Th2 Cell ◽  
Reporter Mice ◽  
Relationship Of ◽  
The Relationship

The relationship of T follicular helper (TFH) cells to other T helper (Th) subsets is controversial. We find that after helminth infection, or immunization with helminth antigens, reactive lymphoid organs of 4get IL-4/GFP reporter mice contain populations of IL-4/GFP-expressing CD4+ T cells that display the TFH markers CXCR5, PD-1, and ICOS. These TFH cells express the canonical TFH markers BCL6 and IL-21, but also GATA3, the master regulator of Th2 cell differentiation. Consistent with a relationship between Th2 and TFH cells, IL-4 protein production, reported by expression of huCD2 in IL-4 dual reporter (4get/KN2) mice, was a robust marker of TFH cells in LNs responding to helminth antigens. Moreover, the majority of huCD2/IL-4–producing Th cells were found within B cell follicles, consistent with their definition as TFH cells. TFH cell development after immunization failed to occur in mice lacking B cells or CD154. The relationship of TFH cells to the Th2 lineage was confirmed when TFH cells were found to develop from CXCR5− PD-1− IL-4/GFP+ CD4+ T cells after their transfer into naive mice and antigen challenge in vivo.

scholarly journals Neoantigen driven B cell and CD4+ T follicular helper cell collaboration promotes robust anti-tumor CD8+ T cell responses

2020 ◽  
Author(s):  
Can Cui ◽  
Jiawei Wang ◽  
Ping-Min Chen ◽  
Kelli A. Connolly ◽  
Martina Damo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Interactions ◽  
Tumor Control ◽  
Cell Responses ◽  
Tfh Cells ◽  
Follicular Helper ◽  
T Follicular Helper Cell

AbstractCD4+ T follicular helper (TFH) cells provide help to B cells, which is critical for germinal center (GC) formation, but the importance of TFH-B cell interactions in cancer is unclear. We found TFH cells correlated with GC B cells and with prolonged survival of lung adenocarcinoma (LUAD) patients. To investigate further, we developed an LUAD model, in which tumor cells expressed B-cell- and T-cell-recognized neoantigens. Interactions between tumor-specific TFH and GC B cells were necessary for tumor control, as were effector CD8+ T cells. The latter were reduced in the absence of T cell-B cell interactions or the IL-21 receptor. IL-21 was produced primarily by TFH cells, development of which required B cells. Moreover, development of tumor-specific TFH cell-responses was also reliant upon tumors that expressed B-cell-recognized neoantigens. Thus, tumor-neoantigens themselves can control the fate decisions of tumor-specific CD4+ T cells by facilitating interactions with tumor-specific B cells.Abstract Figure

scholarly journals TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand

2005 ◽  
Vol 202 (9) ◽  
pp. 1213-1223 ◽  
Author(s):  
Tomoki Ito ◽  
Yui-Hsi Wang ◽  
Omar Duramad ◽  
Toshiyuki Hori ◽  
Guy J. Delespesse ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Th2 Cells ◽  
T Helper ◽  
Cell Responses ◽  
Th Cell ◽  
Tnf Α ◽  
Ox40 Ligand ◽  
Helper Type

We recently showed that dendritic cells (DCs) activated by thymic stromal lymphopoietin (TSLP) prime naive CD4+ T cells to differentiate into T helper type 2 (Th2) cells that produced high amounts of tumor necrosis factor-α (TNF-α), but no interleukin (IL)-10. Here we report that TSLP induced human DCs to express OX40 ligand (OX40L) but not IL-12. TSLP-induced OX40L on DCs was required for triggering naive CD4+ T cells to produce IL-4, -5, and -13. We further revealed the following three novel functional properties of OX40L: (a) OX40L selectively promoted TNF-α, but inhibited IL-10 production in developing Th2 cells; (b) OX40L lost the ability to polarize Th2 cells in the presence of IL-12; and (c) OX40L exacerbated IL-12–induced Th1 cell inflammation by promoting TNF-α, while inhibiting IL-10. We conclude that OX40L on TSLP-activated DCs triggers Th2 cell polarization in the absence of IL-12, and propose that OX40L can switch IL-10–producing regulatory Th cell responses into TNF-α–producing inflammatory Th cell responses.

scholarly journals Human lymphoid organ cDC2 and macrophages play complementary roles in T follicular helper responses

2019 ◽  
Vol 216 (7) ◽  
pp. 1561-1581 ◽  
Author(s):  
Mélanie Durand ◽  
Thomas Walter ◽  
Tiphène Pirnay ◽  
Thomas Naessens ◽  
Paul Gueguen ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lymphoid Organ ◽  
Functional Specialization ◽  
T Helper ◽  
Mass Cytometry ◽  
Effector Molecules ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Humoral Responses

CD4+ T follicular helper (Tfh) cells are essential for inducing efficient humoral responses. T helper polarization is classically orientated by dendritic cells (DCs), which are composed of several subpopulations with distinct functions. Whether human DC subsets display functional specialization for Tfh polarization remains unclear. Here we find that tonsil cDC2 and CD14+ macrophages are the best inducers of Tfh polarization. This ability is intrinsic to the cDC2 lineage but tissue dependent for macrophages. We further show that human Tfh cells comprise two effector states producing either IL-21 or CXCL13. Distinct mechanisms drive the production of Tfh effector molecules, involving IL-12p70 for IL-21 and activin A and TGFβ for CXCL13. Finally, using imaging mass cytometry, we find that tonsil CD14+ macrophages localize in situ in the B cell follicles, where they can interact with Tfh cells. Our results indicate that human lymphoid organ cDC2 and macrophages play complementary roles in the induction of Tfh responses.

scholarly journals Screening and development of monoclonal antibodies for identification of ferret T follicular helper cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wenbo Jiang ◽  
Julius Wong ◽  
Hyon-Xhi Tan ◽  
Hannah G. Kelly ◽  
Paul G. Whitney ◽  
...  
Keyword(s):  
Animal Model ◽  
Monoclonal Antibodies ◽  
Lymph Node ◽  
Cross Reactivity ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Lymph Node Cells ◽  
Human Viruses ◽  
Humoral Responses ◽  
Murine Monoclonal Antibodies

AbstractThe ferret is a key animal model for investigating the pathogenicity and transmissibility of important human viruses, and for the pre‐clinical assessment of vaccines. However, relatively little is known about the ferret immune system, due in part to a paucity of ferret‐reactive reagents. In particular, T follicular helper (Tfh) cells are critical in the generation of effective humoral responses in humans, mice and other animal models but to date it has not been possible to identify Tfh in ferrets. Here, we describe the screening and development of ferret-reactive BCL6, CXCR5 and PD-1 monoclonal antibodies. We found two commercial anti-BCL6 antibodies (clone K112-91 and clone IG191E/A8) had cross-reactivity with lymph node cells from influenza-infected ferrets. We next developed two murine monoclonal antibodies against ferret CXCR5 (clone feX5-C05) and PD-1 (clone fePD-CL1) using a single B cell PCR-based method. We were able to clearly identify Tfh cells in lymph nodes from influenza infected ferrets using these antibodies. The development of ferret Tfh marker antibodies and the identification of ferret Tfh cells will assist the evaluation of vaccine-induced Tfh responses in the ferret model and the design of novel vaccines against the infection of influenza and other viruses, including SARS-CoV2.

scholarly journals Reduced Follicular Regulatory T Cells in Spleen and Pancreatic Lymph Nodes of Patients With Type 1 Diabetes

2021 ◽  
Author(s):  
Andrea Vecchione ◽  
Tatiana Jofra ◽  
Jolanda Gerosa ◽  
Kimberly Shankwitz ◽  
Roberta Di Fonte ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Lymph Nodes ◽  
Organ Donor ◽  
Peripheral Tolerance ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Pancreatic Lymph Nodes ◽  
Cell Alterations ◽  
Humoral Tolerance

In the attempt to understand the origin of autoantibody (AAb) production in patients with and at-risk for T1D, multiple studies have analyzed and reported alterations in follicular helper T cells (Tfh) in presymptomatic AAb-positive subjects and patients with T1D. Yet, it is still not clear whether the regulatory counterpart of Tfh cells, represented by follicular regulatory T cells (Tfr), is similarly altered. To address this question, we performed analyses in peripheral blood, spleen and pancreatic lymph nodes (PLN) of organ donor subjects with T1D. Blood analyses were also performed in living AAb-negative and -positive subjects. While negligible differences in the frequency and phenotype of blood Tfr cells were observed between T1D, AAb-negative and AAb-positive adult subjects, the frequency of Tfr cells was significantly reduced in spleen and PLN of T1D as compared to non-diabetic controls. Furthermore, adoptive transfer of Tfr cells delayed disease development in a mouse model of T1D, a finding that could indicate that Tfr cells play an important role in peripheral tolerance and regulation of autoreactive Tfh cells. Together, our findings provide evidence of Tfr cell alterations within disease-relevant tissues in patients with T1D suggesting a role for Tfr cells in defective humoral tolerance and disease pathogenesis.

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