Th17 Cells and Associated Cytokines in Inflammation and Cancer

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-5-SCI-5
Author(s):  
Chen Dong
Keyword(s):  
T Cells ◽  
Germinal Center ◽  
Th17 Cells ◽  
The Other ◽  
Th Cells ◽  
Tissue Inflammation ◽  
Tfh Cells ◽  
Follicular Helper ◽  
And Function ◽  
Th1 And Th2

Abstract Abstract SCI-5 CD4+ T cells, upon activation, differentiate into cytokine-producing effector helper T (TH) cells. In addition to TH1 and TH2 lineage cells, additional TH subsets, including TH17 and T follicular helper (Tfh) cells have been identified. TH17 cells produce IL-17, IL-17F, IL-21, and IL-22 and mediate tissue inflammation. TH17 cells play protective or pathogenic roles in cancer, depending on the context. On the other hand, Tfh cells produce IL-21 and regulate germinal center reactions. Tfh cells may play a role in some forms of lymphoma. I will discuss on the regulation and function of these two subsets of T cells in the context of cancer. Disclosures: Dong: Ono: Consultancy; Tempero: Consultancy; Genentech: Honoraria; GSK: Consultancy; AnaptysBio: Consultancy.

The Transcriptional Profile of Follicular Lymphoma Associated Regulatory T-Cells (Tregs) Is More Consistent with Tregs Having a Germinal Center Localization and the Ability to Suppress Follicular Helper T-Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1536-1536
Author(s):  
Shannon P. Hilchey ◽  
Alexander F. Rosenberg ◽  
Stephen L. Welle ◽  
Ollivier Hyrien ◽  
Steven H. Bernstein
Keyword(s):  
T Cells ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Germinal Center ◽  
Th17 Cells ◽  
Helper T Cells ◽  
Transcriptome Profile ◽  
Follicular Helper ◽  
Inflammatory Signals ◽  
Lower Expression

Abstract Abstract 1536 Recent studies have suggested that regulatory T-cells (Tregs) play a critical role in the pathogenesis of follicular lymphoma (FL). We have previously shown that the Tregs infiltrating FL lymph nodes (FLN Tregs) are quantitatively and qualitatively different than those infiltrating normal and reactive nodes (NLN, RLN, respectively). To gain insight into how such Treg populations differ, and how FLN Tregs may impact FL progression and response to therapy, we performed RNA sequence analyses on flow sorted Tregs (CD3+CD4+CD25brightCD127−) from NLN (n=10), FLN (n=12) and RLN (n=7). Using the RefSeq annotated set of mRNA we first identified 11686 annotated genes that were expressed in each of the Treg groups. Using pairwise unequal variance t-tests at p<0.01, we identified 798 genes that differed between NLN and FLN, 589 that differed between NLN and RLN, and 475 genes that differed between FLN and RLN. The transcriptome profile of the FLN Tregs differed most from that of NLN Tregs, with 281 genes increased in FLN relative to NLN, and 517 genes decreased in FLN Tregs relative to NLN Tregs. In contrast, 404 genes were increased and 70 genes decreased in RLN Tregs relative to FLN Tregs suggesting that differences in the transcriptome profile between NLN and FLN Tregs are due, in part, to inflammatory signals shared between FLN and RLN. Tregs, which express FOXP3, are a heterogeneous population which share a “core suppressive module” of CD25 and CTLA-4, but which adapt to microenvironmental signals by co-opting/or up-regulating the canonical transcription factor (TF) of the T-cell population the Treg needs to suppress. This results in modulation of the Treg chemokine receptors in such a fashion that allows these Tregs to traffic to and suppress the specific T-cell population defined by their TF expression. Relative to NLN, FLN Tregs have similar expression of FOXP3 and CD25 but greater expression of CTLA-4 (confirmed at the protein level), which may account, in part, for the greater suppressive activity of FLN Tregs compared to NLN Tregs. Expression of other genes that differ between NLN and FLN which encode for proteins that modulate Treg suppression include IL-10 (up in FLN relative to NLN), S1PR1 and ENTPD1 (both down in FLN relative to NLN), which all favor greater suppression by FLN Tregs. In contrast LGALS1 and NT5E expression (both down in FLN relative to NLN) would favor less suppression by FLN Tregs. Relative to NLN, FLN Tregs have greater BCL-6 expression, consistent with a population that suppress follicular helper T-cells (Tfh), which support normal germinal center (GC) and FL-B cell survival. Consistent with their increased expression of BCL-6, FLN Tregs have greater expression of CXCR5, CXCR4 and CXCL13 and decreased expression of CCR7 compared to that of NLN Tregs, a repertoire associated with GC trafficking. The significant lower expression of both S1PR1 and SELL (CD62L; p<0.000002, and fold changes of −9.0 and −2.8, respectively) that is found in FLN Tregs compared to NLN Tregs is consistent with the greater nodal retention. The lower expression of RORc found in the FLN Tregs would predict for decreased IL-17 secretion and their elevated levels of STAT3 which would support the ability of the FLN Tregs to inhibit Th17 cells. In conclusion, the comparison of the transcriptome profiles of FLN and NLN Tregs; a) suggest that the observed differences are shaped, in part, by inflammatory signals also present in RLN; b) lay the foundation of a hypothesis to explain the molecular basis for their greater immunosuppressive capacity; and c) suggest that FL Tregs are ‘poised’ to localize in the GC, be strongly retained in the lymph node and have enhanced potential to suppress Tfh and Th17 cells. Such findings offer new insights into how FL Tregs may contribute to the biology of these B cell lymphomas. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Functional STAT3 deficiency compromises the generation of human T follicular helper cells

Blood ◽  
2012 ◽  
Vol 119 (17) ◽  
pp. 3997-4008 ◽  
Author(s):  
Cindy S. Ma ◽  
Danielle T. Avery ◽  
Anna Chan ◽  
Marcel Batten ◽  
Jacinta Bustamante ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Cd4 T Cells ◽  
Cell Development ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Helper Activity ◽  
And Function

Abstract T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4+ T cells to the Tfh lineage, because IL-12 induces naive human CD4+ T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4+ T cells from patients deficient in IL-12Rβ1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12–induced expression of IL-21 by human CD4+ T cells. Defective expression of IL-21 by STAT3-deficient CD4+ T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4+CXCR5+ T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.

scholarly journals Sphingosine-1-phosphate receptor 2 is critical for follicular helper T cell retention in germinal centers

2014 ◽  
Vol 211 (7) ◽  
pp. 1297-1305 ◽  
Author(s):  
Saya Moriyama ◽  
Noriko Takahashi ◽  
Jesse A. Green ◽  
Shohei Hori ◽  
Masato Kubo ◽  
...  
Keyword(s):  
T Cells ◽  
Germinal Center ◽  
Molecular Mechanisms ◽  
Germinal Centers ◽  
Antibody Responses ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Sphingosine 1 Phosphate ◽  
Follicular Helper T Cell ◽  
Cell Follicle

Follicular helper T (Tfh) cells access the B cell follicle to promote antibody responses and are particularly important for germinal center (GC) reactions. However, the molecular mechanisms of how Tfh cells are physically associated with GCs are incompletely understood. We report that the sphingosine-1-phosphate receptor 2 (S1PR2) gene is highly expressed in a subpopulation of Tfh cells that localizes in GCs. S1PR2-deficient Tfh cells exhibited reduced accumulation in GCs due to their impaired retention. T cells deficient in both S1PR2 and CXCR5 were ineffective in supporting GC responses compared with T cells deficient only in CXCR5. These results suggest that S1PR2 and CXCR5 cooperatively regulate localization of Tfh cells in GCs to support GC responses.

scholarly journals IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells

2010 ◽  
Vol 207 (13) ◽  
pp. 2895-2906 ◽  
Author(s):  
Marcel Batten ◽  
Nandhini Ramamoorthi ◽  
Noelyn M. Kljavin ◽  
Cindy S. Ma ◽  
Jennifer H. Cox ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Germinal Center ◽  
Dependent Manner ◽  
High Affinity ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Cell Clones

Maturation and selection of high-affinity B cell clones in the germinal center (GC) relies on support from T follicular helper (TFH) cells. TFH cells are characterized by their localization to the B cell follicle and their high expression of the costimulatory molecules ICOS and PD1 and the cytokine IL-21, which promotes immunoglobulin (Ig) class switching and production by B cells. We show that the heterodimeric cytokine IL-27 is critical for the function of TFH cells and for normal and pathogenic GC responses. IL-27 signaling to T cells results in the production of IL-21, a known autocrine factor for the maintenance of TFH cells, in a STAT3-dependent manner. IL-27 also enhances the survival of activated CD4+ T cells and the expression of TFH cell phenotypic markers. In vivo, expression of the IL-27Rα chain is required to support IL-21 production and TFH cell survival in a T cell–intrinsic manner. The production of high-affinity antibodies is reduced, and pristane-elicited autoantibodies and glomerulonephritis are significantly diminished, in Il27ra−/− mice. Together, our data show a nonredundant role for IL-27 in the development of T cell–dependent antibody responses.

scholarly journals Granulocytic myeloid-derived suppressor cells inhibit T follicular helper cells during experimental Schistosoma japonicum infection

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yumei Zhang ◽  
Yulong Wu ◽  
Hua Liu ◽  
Wenci Gong ◽  
Yuan Hu ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Th Cells ◽  
Tfh Cells ◽  
Follicular Helper

Abstract Background CD4+ T helper (Th) cells play critical roles in both host humoral and cellular immunity against parasitic infection and in the immunopathology of schistosomiasis. T follicular helper (Tfh) cells are a specialized subset of Th cells involved in immunity against infectious diseases. However, the role of Tfh cells in schistosome infection is not fully understood. In this study, the dynamics and roles of Tfh cell regulation were examined. We demonstrated that granulocytic myeloid-derived suppressor cells (G-MDSC) can suppress the proliferation of Tfh cells. Methods The levels of Tfh cells and two other Th cells (Th1, Th2) were quantitated at different Schistosoma japonicum infection times (0,3, 5, 8, 13 weeks) using flow cytometry. The proliferation of Tfh cells stimulated by soluble egg antigen (SEA) and soluble worm antigen (SWA) in vivo and in vitro were analyzed. Tfh cells were co-cultured with MDSC to detect the proliferation of Tfh cells labelled by 5(6)-carboxyfluorescein diacetate N-succinimidyl ester. We dynamically monitored the expression of programmed cell death protein 1 (PD-1) on the surface of Tfh cells and programmed cell death ligand 1 (PD-L1) on the surface of MDSC at different infection times (0, 3, 5, 8 weeks). Naïve CD4+ T cells (in Tfh cell differentiation) were co-cultured with G-MDSC or monocytic MDSC in the presence, or in the absence, of PD-L1 blocking antibody. Results The proportion of Tfh cells among CD4+ T cells increased gradually with time of S. japonicum infection, reaching a peak at 8 weeks, after which it decreased gradually. Both SEA and SWA caused an increase in Tfh cells in vitro and in vivo. It was found that MDSC can suppress the proliferation of Tfh cells. The expression of PD-1 on Tfh cells and PD-L1 from MDSC cells increased with prolongation of the infection cycle. G-MDSC might regulate Tfh cells through the PD-1/PD-L1 pathway. Conclusions The reported study not only reveals the dynamics of Tfh cell regulation during S. japonicum infection, but also provides evidence that G-MDSC may regulate Tfh cells by PD-1/PD-L1. This study provides strong evidence for the important role of Tfh cells in the immune response to S. japonicum infection. Graphical abstract

Germinal Center Generation and Maintenance By T Follicular Helper Cells Is Required For The Development Of Chronic Gvhd Associated Bronchiolitis Obliterans In a Preclinical Model

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 292-292
Author(s):  
Ryan Flynn ◽  
Jing Du ◽  
Rachelle Veenstra ◽  
Angela Panoskaltsis-Mortari ◽  
Andrew Price ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Germinal Center ◽  
Bronchiolitis Obliterans ◽  
Essential Role ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Target Organs ◽  
Donor T Cells ◽  
Anti Cd20

Abstract Introduction One obstacle that continues to pose a major risk for hematopoietic stem cell transplantation is the occurrence of chronic graft-versus-host disease (cGVHD). Although the exact cause of cGVHD is unknown, preclinical findings have demonstrated a significant increase in class-switched anti-host reactive antibody deposition and fibrosis in target organs. We have previously demonstrated the dependence of cGVHD on donor bone marrow (BM)-derived B cells and splenic-derived T cells in a model of cGVHD that develops bronchiolitis obliterans (BO), a pathognomonic symptom of lung cGVHD (Blood 119:1570-80, 2012). T:B cell pathways responsible for cGVHD have yet to be elucidated. Germinal Center (GC) reactions are dependent on T follicular helper (TFH) cell stimulation and controlled by T follicular regulatory cells (TFR). TFH cells are located in the B-cell zones, express Bcl6, CXCR5, ICOS, and high levels of PD1, and provide stimulation through IL-21 production and ICOS and CD40L expression. TFR are located in the GC and express FoxP3. In this study we define a previously unknown role for TFH cells in the development of cGVHD. Methods B10.BR (H2k) mice were conditioned with cyclophosphamide and irradiation and transplanted with B6 (H2b) BM and mature splenic-derived T cells. After 8 weeks, pulmonary function of the mice was measured during mechanical ventilation using whole body plethymography. BO was defined by low compliance and high elastance and resistance in association with collagen deposition leading to obliterated bronchioles. Target organs (lung, liver, spleen) were analyzed for collagen accumulation, immunoglobulin deposition, size of GCs, frequency and of TFH, GC B cells and TFR. Interventions included use of knockout (KO) donors or administration of monoclonal antibody (mAb) from days 28-56 to treat cGVHD. Results cGVHD is associated with high GC number, TFH cell number and low TFR (Figure 1 A-D). To determine whether TFH cells were required for cGVHD, we transplanted mice with wild-type (WT) BM and WT T cells or T cells deficient for the TFH master regulator Bcl-6. In contrast to WT T cells, recipients of BCL6 KO T cells had no pathogenic antibody deposited in the lung and no evidence of BO (Figure 1 E-H). Recipients of TFH deficient T cells had a significant decrease in the collagen surrounding the bronchioles and in frequency of GC B cells and TFH compared to cGVHD mice. Consistent with an essential role for TFH cells, TFH deficient, CXCR5 KO donor T cells were unable to induce cGVHD. To determine whether the TFH-produced cytokine IL-21 was necessary for cGVHD, donor IL-21 KO T cells with WT BM or WT T cells with IL-21R KO BM-derived B cells did not develop cGVHD. Importantly, therapeutic administration of anti-IL-21 neutralizing mAb (kindly provided by Novo Nordisk, Copenhagen, Denmark) was able to reverse established cGVHD in this model. Studies using TFH-deficient, ICOS KO donor T cells or anti-ICOS blocking mAb beginning day 28 as cGVHD therapy confirmed the requirement for ICOS:ICOS ligand signaling in cGVHD generation and maintenance. Moreover, blocking CD40L:CD40 interactions in mice with established cGVHD using anti-CD40L blocking mAb was effective in reversing cGVHD. Lastly, studies using a highly B cell depleting anti-CD20 mAb for cGVHD therapy suggested that plasmablasts and plasma cells derived from GC B cells were critical for continued pathogenic Ab production as cGVHD was not reversed by anti-CD20 mAb in this model system. However, it is unknown if prophylactic treatment with anti-CD20 mAb is effective for preventing onset of disease. Conclusions These data provide novel insights into cGVHD pathogenesis, indicating the essential role of TFH in these processes and suggest new lines of therapy using mAb that target TFH cells, GC B cells, and their interactions, with the potential to reverse established pulmonary cGVHD. Disclosures: Browning: Biogen Idec: Employment.

Single Cell Profiling Reveals Unique CXCL13 Positive T Cell Subsets in the Tumor Microenvironment of Lymphocyte Rich Classic Hodgkin Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Tomohiro Aoki ◽  
Lauren C. Chong ◽  
Katsuyoshi Takata ◽  
Katy Milne ◽  
Elizabeth Chavez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Single Cell ◽  
Immune Cells ◽  
Research Funding ◽  
Immune Cell ◽  
Expression Patterns ◽  
The Other ◽  
Tfh Cells

Introduction: Classic Hodgkin lymphoma (CHL) features a unique crosstalk between malignant cells and different types of normal immune cells in the tumor-microenvironment (TME). On the basis of histomorphologic and immunophenotypic features of the malignant Hodgkin and Reed-Sternberg (HRS) cells and infiltrating immune cells, four histological subtypes of CHL are recognized: Nodular sclerosing (NS), Mixed cellularity, Lymphocyte-rich (LR) and Lymphocyte-depleted CHL. Recently, our group described the high abundance of various types of immunosuppressive CD4+ T cells including LAG3+ and/or CTLA4+ cells in the TME of CHL using single cell RNA sequencing (scRNAseq). However, the TME of LR-CHL has not been well characterized due to the rarity of the disease. In this study, we aimed at characterizing the immune cell profile of LR-CHL at single cell resolution. METHODS: We performed scRNAseq on cell suspensions collected from lymph nodes of 28 primary CHL patients, including 11 NS, 9 MC and 8 LR samples, with 5 reactive lymph nodes (RLN) serving as normal controls. We merged the expression data from all cells (CHL and RLN) and performed batch correction and normalization. We also performed single- and multi-color immunohistochemistry (IHC) on tissue microarray (TMA) slides from the same patients. In addition, an independent validation cohort of 31 pre-treatment LR-CHL samples assembled on a TMA, were also evaluated by IHC. Results: A total of 23 phenotypic cell clusters were identified using unsupervised clustering (PhenoGraph). We assigned each cluster to a cell type based on the expression of genes described in published transcriptome data of sorted immune cells and known canonical markers. While most immune cell phenotypes were present in all pathological subtypes, we observed a lower abundance of regulatory T cells (Tregs) in LR-CHL in comparison to the other CHL subtypes. Conversely, we found that B cells were enriched in LR-CHL when compared to the other subtypes and specifically, all four naïve B-cell clusters were quantitatively dominated by cells derived from the LR-CHL samples. T follicular helper (TFH) cells support antibody response and differentiation of B cells. Our data show the preferential enrichment of TFH in LR-CHL as compared to other CHL subtypes, but TFH cells were still less frequent compared to RLN. Of note, Chemokine C-X-C motif ligand 13 (CXCL13) was identified as the most up-regulated gene in LR compared to RLN. CXCL13, which is a ligand of C-X-C motif receptor 5 (CXCR5) is well known as a B-cell attractant via the CXCR5-CXCL13 axis. Analyzing co-expression patterns on the single cell level revealed that the majority of CXCL13+ T cells co-expressed PD-1 and ICOS, which is known as a universal TFH marker, but co-expression of CXCR5, another common TFH marker, was variable. Notably, classical TFH cells co-expressing CXCR5 and PD-1 were significantly enriched in RLN, whereas PD-1+ CXCL13+ CXCR5- CD4+ T cells were significantly enriched in LR-CHL. These co-expression patterns were validated using flow cytometry. Moreover, the expression of CXCR5 on naïve B cells in the TME was increased in LR-CHL compared to the other CHL subtypes We next sought to understand the spatial relationship between CXCL13+ T cells and malignant HRS cells. IHC of all cases revealed that CXCL13+ T cells were significantly enriched in the LR-CHL TME compared to other subtypes of CHL, and 46% of the LR-CHL cases showed CXCL13+ T cell rosettes closely surrounding HRS cells. Since PD-1+ T cell rosettes are known as a specific feature of LR-CHL, we confirmed co-expression of PD-1 in the rosetting cells by IHC in these cases. Conclusions: Our results reveal a unique TME composition in LR-CHL. LR-CHL seems to be distinctly characterized among the CHL subtypes by enrichment of CXCR5+ naïve B cells and CD4+ CXCL13+ PD-1+ T cells, indicating the importance of the CXCR5-CXCL13 axis in the pathogenesis of LR-CHL. Figure Disclosures Savage: BeiGene: Other: Steering Committee; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy. Scott:Janssen: Consultancy, Research Funding; Celgene: Consultancy; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy. Steidl:AbbVie: Consultancy; Roche: Consultancy; Curis Inc: Consultancy; Juno Therapeutics: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Research Funding.

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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