An overview of T follicular cells in transplantation: spotlight on their clinical significance

Niu, Qian; Kraaijeveld, Rens; Li, Yi; Rojas, Aleixandra Mendoza; Shi, Yunying; Wang, Lanlan; Besouw, Nicole M. van; Baan, Carla C.

doi:10.1080/1744666x.2020.1693262

Cited by 4 publications

(5 citation statements)

References 130 publications

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“…However, elucidating each agent’s effect is substantially confounded by the use of other drugs and frequent clinician adjustment in the context of rejection, infection etc. There has also been a trend in some studies ( 100 ) of a positive Tfr : Tfh associating with less DSA formation. However, Niu et al.…”

Section: Role Of Tfr In Human Diseasesmentioning

confidence: 87%

“…While these studies involving immunosuppression are confounded by small patient numbers, differences in HLA typing and variation in immunosuppression regimes, there is a consistent finding that a positive ratio of Tfr : Tfh correlates with immune regulation and a trend toward less DSA formation. Niu et al (100) observed that kidney transplant recipients on immunosuppressive therapy with tacrolimus (Tac), mycophenolate mofetil (MMF), and steroids, with anti-HLA antibodies including DSA had lower numbers of circulating Tfr (CD3 + CD4 + CXCR5 + FOXP3 + ) cells than patients without anti-HLA antibodies. Inverse correlations between the kidney function parameters (serum creatinine level), and number of circulating Tfr cells and number of Helios+ circulating Tfr cells were found, indicating that the reduction of number of bTfr cells might reflect the lack of regulation of active B cell immunit directed against the allograft in kidney transplant recipients.…”

Section: Longer-term Immunosuppressionmentioning

confidence: 99%

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Potential Application of T-Follicular Regulatory Cell Therapy in Transplantation

et al. 2021

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Regulatory T cells (Tregs) constitute a small proportion of circulating CD4+ T cells that function to maintain homeostasis and prevent autoimmunity. In light of their powerful immunosuppressive and tolerance-promoting properties, Tregs have become an interesting potential candidate for therapeutic use in conditions such as solid organ transplant or to treat autoimmune and inflammatory conditions. Clinical studies have demonstrated the safety of polyclonally expanded Tregs in graft-versus-host disease, type 1 diabetes, and more recently in renal and liver transplantation. However, Tregs are heterogenous. Recent insights indicate that only a small proportion of Tregs, called T follicular regulatory cells (Tfr) regulate interactions between B cells and T follicular helper (Tfh) cells within the germinal center. Tfr have been mainly described in mouse models due to the challenges of sampling secondary lymphoid organs in humans. However, emerging human studies, characterize Tfr as being CD4+CD25+FOXP3+CXCR5+ cells with different levels of PD-1 and ICOS expression depending on their localization, in the blood or the germinal center. The exact role they play in transplantation remains to be elucidated. However, given the potential ability of these cells to modulate antibody responses to allo-antigens, there is great interest in exploring translational applications in situations where B cell responses need to be regulated. Here, we review the current knowledge of Tfr and the role they play focusing on human diseases and transplantation. We also discuss the potential future applications of Tfr therapy in transplantation and examine the evidence for a role of Tfr in antibody production, acute and chronic rejection and tertiary lymphoid organs. Furthermore, the potential impact of immunosuppression on Tfr will be explored. Based on preclinical research, we will analyse the rationale of Tfr therapy in solid organ transplantation and summarize the different challenges to be overcome before Tfr therapy can be implemented into clinical practice.

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Section: Role Of Tfr In Human Diseasesmentioning

confidence: 87%

Section: Longer-term Immunosuppressionmentioning

confidence: 99%

Potential Application of T-Follicular Regulatory Cell Therapy in Transplantation

et al. 2021

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“…MMF is a known inhibitor of lymphocyte proliferation ( 46 ) and calcineurin inhibitors have an adverse effect on the differentiation and function of regulatory T cells ( 47 – 49 ). Circulating Tfr cells are primarily derived from Tregs ( 50 ) so it stands to reason that if Treg differentiation is inhibited then this may also have a direct effect on cTfr cell numbers.…”

Section: Discussionmentioning

confidence: 99%

Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients

et al. 2020

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Background: FoxP3 + follicular regulatory T cells (Tfr) have been identified as the cell population controlling T follicular helper (Tfh) cells and B cells which, are both involved in effector immune responses against transplanted tissue. Methods: To understand the biology of Tfr cells in kidney transplant patients treated with tacrolimus and mycophenolate mofetil (MMF) combination immunosuppression, we measured circulating (c)Tfh and cTfr cells in peripheral blood by flow cytometry in n = 211 kidney transplant recipients. At the time of measurement patients were 5–7 years after transplantation. Of this cohort of patients, 23.2% (49/211) had been previously treated for rejection. Median time after anti-rejection therapy was 4.9 years (range 0.4–7 years). Age and gender matched healthy individuals served as controls. Results: While the absolute numbers of cTfh cells were comparable between kidney transplant recipients and healthy controls, the numbers of cTfr cells were 46% lower in immunosuppressed recipients ( p < 0.001). More importantly, in transplanted patients, the ratio of cTfr to cTfh was decreased (median; 0.10 vs. 0.06), indicating a disruption of the balance between cTfr and cTfh cells. This shifted balance was observed for both non-rejectors and rejectors. Previous pulse methylprednisolone or combined pulse methylprednisolone + intravenous immunoglobulin anti-rejection therapy led to a non-significant 30.6% (median) and 51.2% (median) drop in cTfr cells, respectively when compared to cTfr cell numbers in transplant patients who did not receive anti-rejection therapy. A history of alemtuzumab therapy did lead to a significant decrease in cTfr cells of 85.8% (median) compared with patients not treated with anti-rejection therapy ( p < 0.0001). No association with tacrolimus or MMF pre-dose concentrations was found. Conclusion: This cross-sectional study reveals that anti-rejection therapy with alemtuzumab significantly lowers the number of cTfr cells in kidney transplant recipients. The observed profound effects by these agents might dysregulate cTfr functions.

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“…Tfh and Tfr cells are currently being used as biomarkers and therapeutic targets in various clinical settings, including cancer and transplantation (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). A clear understanding of the mechanisms that control the development of Tfh and Tfr cells and the factors that contribute to GC responses is vital to the success of Tfh-based immune-monitoring and therapy development.…”

Section: Editorial On the Research Topic Follicular Helper T Cells Inmentioning

confidence: 99%

Editorial: Follicular Helper T Cells in Immunity and Autoimmunity

2020

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An overview of T follicular cells in transplantation: spotlight on their clinical significance

Cited by 4 publications

References 130 publications

Potential Application of T-Follicular Regulatory Cell Therapy in Transplantation

Potential Application of T-Follicular Regulatory Cell Therapy in Transplantation

Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients

Editorial: Follicular Helper T Cells in Immunity and Autoimmunity

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