Somatic mutations and affinity maturation are impaired by excessive numbers of T follicular helper cells and restored by Treg cells or memory T cells

Preite, Silvia; Baumjohann, Dirk; Foglierini, Mathilde; Basso, Camilla; Ronchi, Francesca; Rodriguez, Blanca M. Fernandez; Corti, Davide; Lanzavecchia, Antonio; Sallusto, Federica

doi:10.1002/eji.201545920

Cited by 27 publications

(30 citation statements)

References 35 publications

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“…Consistent with these results, Tfr cells are expanded in PD‐1 deficient compared to WT mice, and transfer of circulating Tfr cells from blood into Tcra −/− recipients also resulted in a marked decrease in the serum antibody response to NP‐OVA immunization . Taken together, these and other reconstitution experiments suggest that Treg and Tfr cells suppress the GC response. However, the results from these experiments may have been influenced by the cytokine environment in T‐cell deficient hosts and the lymphopenia‐induced proliferation of transferred cells, particularly Treg cells, which are highly sensitive to IL‐2 levels .…”

supporting

confidence: 75%

Disentangling Tfr cells from Treg cells and Tfh cells: How to untie the Gordian knot

Amiezer

Phan

2016

Eur J Immunol

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Legend has it that when Gordias, a peasant farmer, rode his oxcart into the capital he was proclaimed the new king of Phrygia by an oracle. In gratitude, he tied his oxcart to a post and dedicated it as an offering to Zeus. The knot was so intricate that it resisted all attempts to untie it, and the oracle prophesied that whoever could untie it would rule over all of Asia. In 333 BC, Alexander the Great came upon the knot and, realizing it had no free ends, took his sword and cut it free. Since their first description in 2004+ T follicular regulatory (Tfr) cells have also resisted all attempts to disentangle them from T follicular helper (Tfh) cells and regulatory T (Treg) cells (Fig. 1). In subsequent landmark studies, Tfr cells were defined as a subset of thymic-derived, FOXP3 + natural Treg cells that are dependent on BCL6 and expression of the chemokine receptor CXCR5 to localize in the germinal center (GC) of the B-cell follicle [2-4]. However, while there was initial consensus on the origin and phenotype of these cells, there was some disagreement on their actual role in the antibody response. This discrepancy may have arisen because these studies

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supporting

confidence: 75%

Disentangling Tfr cells from Treg cells and Tfh cells: How to untie the Gordian knot

Amiezer

Phan

2016

Eur J Immunol

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“…Increased baseline GCs may prevent effective new responses; however, we saw severe defects in older mice regardless of the size of their baseline polyclonal GCs and frequency of naïve IgD + B cells . Alternatively, increased PI3K signaling in B cells could mimic uncontrolled Tfh cell help and loss of GC competitiveness, as shown in the presence of high numbers of Tfh cells . Moreover, FOXO1 may also play a major role in these altered responses.…”

Section: Pi3k Orchestrates Gc B–cell Differentiation and Functionmentioning

confidence: 83%

“…Thus, Pik3cd E1020K/+ Tfh cells may not home nor function properly, which may contribute to highly disorganized GCs, particularly in the context of chronic stimulation (see below). Furthermore, increased numbers of Tfh cells, itself, have detrimental effects on GC B–cell selection and affinity maturation; high numbers of Tfh cells in intact Pik3cd E1020K/+ mice could therefore directly contribute to the defective humoral responses seen after immunization.…”

Section: Tfh‐cell Functional Responsesmentioning

confidence: 99%

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

Preite

Gómez-Rodríguez

Cannons

et al. 2019

Immunological Reviews

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Phosphatidylinositol 3 kinases (PI3K) are a family of lipid kinases that are activated by a variety of cell-surface receptors, and regulate a wide range of downstream readouts affecting cellular metabolism, growth, survival, differentiation, adhesion, and migration. The importance of these lipid kinases in lymphocyte signaling has recently been highlighted by genetic analyses, including the recognition that both activating and inactivating mutations of the catalytic subunit of PI3Kδ, p110δ, lead to human primary immunodeficiencies. In this article, we discuss how studies on the human genetic disorder "Activated PI3K-delta syndrome" and mouse models of this disease (Pik3cd E1020K/+ mice) have provided fundamental insight into pathways regulated by PI3Kδ in T and B cells and their contribution to lymphocyte function and disease, including responses to commensal bacteria and the development of autoimmunity and tumors. We highlight critical roles of PI3Kδ in T follicular helper cells and the orchestration of the germinal center reaction, as well as in CD8 + T-cell function. We further present data demonstrating the ability of the AKT-resistant FOXO1 AAA mutant to rescue IgG1 class switching defects in Pik3cd E1020K/+ B cells, as well as data supporting a role for PI3Kδ in promoting multiple T-helper effector cell lineages. K E Y W O R D S APDS/PASLI, autoimmunity, immunodeficiency, phosphatidylinositol 3 kinase, T and B lymphocytes | 155 PREITE ET al. | AC TIVATED PI3K-DELTA SYNDROMEIn 2013-2014, three studies described immunodeficient patients with heterozygous gain-of-function autosomal-dominant mutations in PIK3CD, the gene encoding the catalytic subunit of PI3K p110δ. [3][4][5] At least 11 mutations have now been identified by whole exome sequencing, with the E1021K mutant being most prevalent. 2,6 Based on similar mutations in PI3Kα found in cancers and overgrowth syndromes, p110δ mutations were predicted to activate p110δ. 4,7 Indeed, increased PI3K activity and downstream readouts including increased PIP 3 levels, pAKT and pS6, have been observed in cells from these patients. 3,4 This novel PID has been named "Activated PI3K-delta syndrome" (APDS) or "p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency" (PASLI), hereafter referred to as APDS. Activated PI3K-delta syndrome is a combined immunodeficiency syndrome characterized by altered T-and B-cell development and responses. APDS is associated with frequent respiratory infections, progressive blood lymphopenia, mucosal lymphoid nodules, defective antibody responses, and lymphoma development. 2 Patients exhibit a paucity of naïve peripheral blood T cells with a large fraction of T cells displaying activation markers. In contrast, B-cell development is partially blocked, with increased transitional and few circulating memory B cells. 4,8,9 Recurrent respiratory infections are the most common feature of APDS. However, Epstein-Barr virus (EBV) and/ or cytomegalovirus (CMV) viremia occurs in a substantial fraction of patients, ...

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“…Perhaps pharmacological manipulation of the A2a receptor during different time points following vaccination could modulate the magnitude and/or epitope specificity for responding B cells to difficult immunogens such as candidate flu and HIV vaccines. Moreover, it is also a possibility that stimulating A2aR during established GC reactions for certain immunogens may help guide affinity maturation, as excessive T cell help has been shown to impair this process (41).…”

Section: Discussionmentioning

confidence: 99%

The GS Protein-coupled A2a Adenosine Receptor Controls T Cell Help in the Germinal Center

Abbott

Silva

Labuda

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillT follicular helper (T FH ) cells have been shown to be critically required for the germinal center (GC) reaction where B cells undergo class switch recombination and clonal selection to generate high affinity neutralizing antibodies. However, detailed knowledge of the physiological cues within the GC microenvironment that regulate T cell help is limited. The cAMP-elevating, G s protein-coupled A2a adenosine receptor (A2aR) is an evolutionarily conserved receptor that limits and redirects cellular immunity. However, the role of A2aR in humoral immunity and B cell differentiation is unknown. We hypothesized that the hypoxic microenvironment within the GC facilitates an extracellular adenosinerich milieu, which serves to limit T FH frequency and function, and also promotes immunosuppressive T follicular regulatory cells (T FR ). In support of this hypothesis, we found that following immunization, mice lacking A2aR (A2aRKO) exhibited a significant expansion of T follicular cells, as well as increases in T FH to T FR ratio, GC T cell frequency, GC B cell frequency, and class switching of GC B cells to IgG1. Transfer of CD4 T cells from A2aRKO or wild type donors into T cell-deficient hosts revealed that these increases were largely T cell-intrinsic. Finally, injection of A2aR agonist, CGS21680, following immunization suppressed T follicular differentiation, GC B cell frequency, and class switching of GC B cells to IgG1. Taken together, these observations point to a previously unappreciated role of G S protein-coupled A2aR in regulating humoral immunity, which may be pharmacologically targeted during vaccination or pathological states in which GC-derived autoantibodies contribute to the pathology.

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Somatic mutations and affinity maturation are impaired by excessive numbers of T follicular helper cells and restored by Treg cells or memory T cells

Cited by 27 publications

References 35 publications

Disentangling Tfr cells from Treg cells and Tfh cells: How to untie the Gordian knot

Disentangling Tfr cells from Treg cells and Tfh cells: How to untie the Gordian knot

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

The GS Protein-coupled A2a Adenosine Receptor Controls T Cell Help in the Germinal Center

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