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A rational strategy to achieve optimal vaccine responses is to potentiate Tfh cells and the germinal center response. This work shows the adjuvant GLA-SE enhances circulating Tfh cells and enduring antibody responses to a malaria vaccine in Tanzanian adults., The generation of protective humoral immunity after vaccination relies on the productive interaction between antigen-specific B cells and T follicular helper (Tfh) cells. Despite the central role of Tfh cells in vaccine responses, there is currently no validated way to enhance their differentiation in humans. From paired human lymph node and blood samples, we identify a population of circulating Tfh cells that are transcriptionally and clonally similar to germinal center Tfh cells. In a clinical trial of vaccine formulations, circulating Tfh cells were expanded in Tanzanian volunteers when an experimental malaria vaccine was adjuvanted in GLA-SE but not when formulated in Alum. The GLA-SE–formulated peptide was associated with an increase in the extrafollicular antibody response, long-lived antibody production, and the emergence of public TCRβ clonotypes in circulating Tfh cells. We demonstrate that altering vaccine adjuvants is a rational approach for enhancing Tfh cells in humans, thereby supporting the long-lived humoral immunity that is required for effective vaccines., Graphical Abstract

Background: T follicular helper (Tfh) cells are key players in the production of antibody-producing B cells via the germinal center reaction. Therapeutic strategies targeting Tfh cells are important where antibody formation is implicated in disease, such as transplant rejection and autoimmune diseases. We investigated the impact of the immunosuppressive agent tacrolimus on human Tfh cell differentiation and function in transplant recipients. Methods: Paired blood and lymph node (LN) samples were obtained from 61 transplant recipients immediately prior to organ implantation. Living-donor recipients received a week of tacrolimus prior to kidney transplantation. Deceased-donor recipients served as controls, as tacrolimus was not administered until after the transplant operation. Flow cytometry was used to compare LN and circulating cell subsets. Results: The calcineurin inhibitor (CNIs) tacrolimus specifically suppresses both LN Tfh cells and circulating Tfh cells, but not their regulatory counterparts or other CD4 T cell subsets. Conclusion: Our findings suggest that CNIs may have a more important role in the prevention of antibody formation than previously understood and, therefore, have potential for antibody-associated conditions in which aberrant Tfh function has been implicated in disease.

De novo donor-specific antibody (DSA) formation is a major problem in transplantation, and associated with long-term graft decline and loss as well as sensitization, limiting future transplant options. Forming high-affinity, long-lived antibody responses involves a process called the germinal center (GC) reaction, and requires interaction between several cell types, including GC B cells, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. T follicular regulatory cells are an essential component of the GC reaction, limiting its size and reducing nonspecific or self-reactive responses.An imbalance between helper function and regulatory function can lead to excessive antibody production. High proportions of Tfh cells have been associated with DSA formation in transplantation; therefore, Tfr cells are likely to play an important role in limiting DSA production. Understanding the signals that govern Tfr cell development and the balance between helper and regulatory function within the GC is key to understanding how these cells might be manipulated to reduce the risk of DSA development.This review discusses the development and function of Tfr cells and their relevance to transplantation. In particular how current and future immunosuppressive strategies might allow us to skew the ratio between Tfr and Tfh cells to increase or decrease the risk of de novo DSA formation.

Background - T follicular helper (Tfh) and regulatory (Tfr) cells are key players in the formation of long-lived antibody responses. Their circulating counterparts, cTfh and cTfr, are often used as biomarkers because longitudinal sampling of secondary lymphoid tissues is unfeasible in clinical studies. This is the first study to track cTfh and cTfr cells following therapeutic lymphocyte depletion with alemtuzumab, an anti-CD52 monoclonal antibody, to infer the influence of this treatment on the germinal centre response. Methods - Samples from 61 transplant recipients were taken at the time of transplant, and regular intervals post-transplant for both flow-cytometric immunophenotyping, and Luminex-based donor-specific antibody (DSA) assessment. Results - Patients treated with alemtuzumab (42/61, 69%) had a significantly lower ratio of cTfr to cTfh at all time points post-transplant. We found that, despite a high proportion of Tregs in the recovering cell population, cTfr cells did not repopulate in alemtuzumab treated patients, while cTfh cells reconstituted to higher than pre-transplant levels over the 2-year follow-up. Conclusions - Alemtuzumab has been used as first-line induction immunosuppression and treatment for steroid-resistant rejection in transplantation; our data suggests alemtuzumab-treated patients have a lower cTfr to cTfh ratio even 2 years post-transplant, and may therefore be at higher risk of de novo DSA formation.

The monoclonal anti-CD20 antibody rituximab (RTX) depletes B cells in the treatment of lymphoma and autoimmune disease, and contributes to alloantibody reduction in transplantation across immunologic barriers. The effects of RTX on T cells are less well described. T-follicular helper (Tfh) cells provide growth and differentiation signals to germinal center (GC) B cells to support antibody production, and suppressive T-follicular regulatory (Tfr) cells regulate this response. In mice, both Tfh and Tfr are absolutely dependent on B cells for their formation and on the GC for their maintenance. In this study, we demonstrate that RTX treatment results in a lack of GC B cells in human lymph nodes without affecting the Tfh or Tfr cell populations. These data demonstrate that human Tfh and Tfr do not require an ongoing GC response for their maintenance. The persistence of Tfh and Tfr following RTX treatment may permit rapid reconstitution of the pathological GC response once the B-cell pool begins to recover. Strategies for maintaining remission after RTX therapy will need to take this persistence of Tfh into account.