Vaccination is an excellent strategy to limit the morbidity and mortality associated with infectious disease. Vaccination creates protective, long-lived antibody-mediated immunity by inducing the ...germinal centre response, an intricate immune reaction that produces memory B cells and long-lived antibody-secreting plasma cells that provide protection against (re)infection. The magnitude and quality of the germinal centre response declines with age, contributing to poor vaccine-induced immunity in older individuals. T follicular helper cells are essential for the formation and function of the germinal centre response. This review will discuss how age-dependent changes in T follicular helper cells influence the germinal centre response, and the evidence that age-dependent changes need not be a barrier to successful vaccination in the later years of life.
The germinal center (GC) is a specialized microstructure that forms in secondary lymphoid tissues, producing long-lived antibody secreting plasma cells and memory B cells, which can provide ...protection against reinfection. Within the GC, B cells undergo somatic mutation of the genes encoding their B cell receptors which, following successful selection, can lead to the emergence of B cell clones that bind antigen with high affinity. However, this mutation process can also be dangerous, as it can create autoreactive clones that can cause autoimmunity. Because of this, regulation of GC reactions is critical to ensure high affinity antibody production and to enforce self-tolerance by avoiding emergence of autoreactive B cell clones. A productive GC response requires the collaboration of multiple cell types. The stromal cell network orchestrates GC cell dynamics by controlling antigen delivery and cell trafficking. T follicular helper (Tfh) cells provide specialized help to GC B cells through cognate T-B cell interactions while Foxp3
T follicular regulatory (Tfr) cells are key mediators of GC regulation. However, regulation of GC responses is not a simple outcome of Tfh/Tfr balance, but also involves the contribution of other cell types to modulate the GC microenvironment and to avoid autoimmunity. Thus, the regulation of the GC is complex, and occurs at multiple levels. In this review we outline recent developments in the biology of cell subsets involved in the regulation of GC reactions, in both secondary lymphoid tissues, and Peyer's patches (PPs). We discuss the mechanisms which enable the generation of potent protective humoral immunity whilst GC-derived autoimmunity is avoided.
T follicular regulatory (Tfr) cells are a subset of Foxp3(+) regulatory T (Treg) cells that form in response to immunization or infection, which localize to the germinal centre where they control the ...magnitude of the response. Despite an increased interest in the role of Tfr cells in humoral immunity, many fundamental aspects of their biology remain unknown, including whether they recognize self- or foreign antigen. Here we show that Tfr cells can be specific for the immunizing antigen, irrespective of whether it is a self- or foreign antigen. We show that, in addition to developing from thymic derived Treg cells, Tfr cells can also arise from Foxp3(-) precursors in a PD-L1-dependent manner, if the adjuvant used is one that supports T-cell plasticity. These findings have important implications for Tfr cell biology and for improving vaccine efficacy by formulating vaccines that modify the Tfr:Tfh cell ratio.
•Older people are more susceptible to poor health outcomes after infection.•Ageing is associated with reduced antibody titres in response to vaccination, limiting vaccine efficacy.•A key contributing ...factor to the poor humoral immunity in ageing is the reduced size and function of the germinal centre response.•The diminished germinal centre response in ageing can be attributed to changes in many of the cellular players involved in the response.
Vaccines are a highly effective intervention for conferring protection against infections and reducing the associated morbidity and mortality in vaccinated individuals. However, ageing is often associated with a functional decline in the immune system that results in poor antibody production in older individuals after vaccination. A key contributing factor of this age-related decline in vaccine efficacy is the reduced size and function of the germinal centre (GC) response. GCs are specialised microstructures where B cells undergo affinity maturation and diversification of their antibody genes, before differentiating into long-lived antibody-secreting plasma cells and memory B cells. The GC response requires the coordinated interaction of many different cell types, including B cells, T follicular helper (Tfh) cells, T follicular regulatory (Tfr) cells and stromal cell subsets like follicular dendritic cells (FDCs). This review discusses how ageing affects different components of the GC reaction that contribute to its limited output and ultimately impaired antibody responses in older individuals after vaccination. An understanding of the mechanisms underpinning the age-related decline in the GC response is crucial in informing strategies to improve vaccine efficacy and extend the healthy lifespan amongst older people.
Cbls boost B cells Linterman, Michelle A
The Journal of experimental medicine,
09/2020, Letnik:
217, Številka:
9
Journal Article
Recenzirano
Odprti dostop
T cell regulation of antibody-mediated immunity is critical for health. In this issue of JEM, Li et al. (https://doi.org/10.1084/jem.20191537) identify the Cbl family of E3 ubiquitin ligases as B ...cell-intrinsic gatekeepers of T cell-dependent humoral immunity.
Follicular Helper T Cells Vinuesa, Carola G; Linterman, Michelle A; Yu, Di ...
Annual review of immunology,
05/2016, Letnik:
34, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Although T cell help for B cells was described several decades ago, it was the identification of CXCR5 expression by B follicular helper T (Tfh) cells and the subsequent discovery of their dependence ...on BCL6 that led to the recognition of Tfh cells as an independent helper subset and accelerated the pace of discovery. More than 20 transcription factors, together with RNA-binding proteins and microRNAs, control the expression of chemotactic receptors and molecules important for the function and homeostasis of Tfh cells. Tfh cells prime B cells to initiate extrafollicular and germinal center antibody responses and are crucial for affinity maturation and maintenance of humoral memory. In addition to the roles that Tfh cells have in antimicrobial defense, in cancer, and as HIV reservoirs, regulation of these cells is critical to prevent autoimmunity. The realization that follicular T cells are heterogeneous, comprising helper and regulatory subsets, has raised questions regarding a possible division of labor in germinal center B cell selection and elimination.
Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the ...host: influenza A virus infection-induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ. Here, we show that type I IFN produced after viral infection can induce CXCL13 expression in a phenotypically distinct population of lung fibroblasts, driving CXCR5-dependent recruitment of B cells and initiating ectopic germinal center formation. This identifies type I IFN as a novel inducer of CXCL13, which, in combination with other stimuli, can promote lung remodeling, converting a nonlymphoid tissue into one permissive to functional tertiary lymphoid structure formation.
• Stromal cells support the initiation, maintenance and output of germinal centre responses.• Fibroblasts are key mediators of tertiary lymphoid structure assembly in non-lymphoid tissues.• Activated ...lung resident fibroblasts mediate lymphocyte recruitment for ectopic germinal centre formation.• Follicular-like stroma can support cross-reactive germinal centres in the lung.
The germinal centre (GC) is a specialized cellular structure that forms in response to antigenic stimulation. It generates long-term humoral immunity through the production of memory B cells and long-lived antibody-secreting plasma cells. Conventional GCs form within secondary lymphoid organs, where networks of specialised stromal cells that form during embryogenesis act as the stage upon which the various GC immune cell players are brought together, nurtured and co-ordinated to generate a productive response. In non-lymphoid organs, ectopic GCs can form in response to persistent antigenic and inflammatory stimuli. Unlike secondary lymphoid tissues, non-lymphoid organs do not have a developmentally programmed stromal cell network capable of supporting the germinal centre reaction; therefore, the local tissue stroma must be remodelled by inflammatory stimuli in order to host a GC reaction. These ectopic GCs produce memory B cells and plasma cells that form a critical component of the humoral immune response.
T follicular helper (Tfh) cells cognately guide differentiation of antigen-primed B cells in secondary lymphoid tissues. ‘Tfh-like’ populations not expressing the canonical Tfh cell transcription ...factor BCL6 have also been described, which can aid particular aspects of B cell differentiation. Tfh and Tfh-like cells are essential for protective and pathological humoral immunity. These CD4+ T cells that help B cells are polarized to produce diverse combinations of cytokines and chemokine receptors and can be grouped into distinct subsets that promote antibodies of different isotype, affinity, and duration, according to the nature of immune challenge. However, unified nomenclature to describe the distinct functional Tfh and Tfh-like cells does not exist. While explicitly acknowledging cellular plasticity, we propose categorizing these cell states into three groups based on phenotype and function, paired with their anatomical site of action.
We propose a group 1, 2, and 3 classification system for CD4+ T cells that help B cells based on differential expression of signature cytokines, transcription factors, and chemokine receptors, paralleling nomenclatures used for other lymphoid subsets.This nomenclature is applicable to BCL6-dependent T follicular helper (Tfh) cells but also BCL6-independent Tfh-like cells that specifically help B cells and are functional in a variety of anatomical sites.These three groups of Tfh/Tfh-like cells induce distinct types of B cell responses.This concept does not exclude cellular plasticity, either between the three groups or between Tfh cells and other effector CD4+ T cell types.
Immune responses demonstrate a high level of intra-species variation, compensating for the specialization capacity of pathogens. The recent advent of in-depth immune phenotyping projects in ...large-scale cohorts has allowed a first look into the factors that shape the inter-individual diversity of the human immune system. Genetic approaches have identified genetic diversity as drivers of 20⿿40% of the variation between the immune systems of individuals. The remaining 60⿿80% is shaped by intrinsic factors, with age being the predominant factor, as well as by environmental influences, where cohabitation and chronic viral infections were identified as key mediators. We review and integrate the recent in-depth large-scale studies on human immune diversity and its potential impact on health. Video Abstract
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