Antibody production is an important feature of the vertebrate immune system. Antibodies neutralize and clear pathogens, thereby protecting against infectious diseases. Such humoral immunity has great ...longevity, often persisting for the host's lifetime. Long-lived humoral immunity depends on help provided by CD4(+) T cells, namely T follicular helper (TFH) cells, which support the differentiation of antigen-specific B cells into memory and plasma cells. TFH cells are stringently regulated, as aberrant TFH cell activity is involved in immunopathologies such as autoimmunity, immunodeficiencies and lymphomas. The elucidation of the mechanisms that regulate TFH cell differentiation, function and fate should highlight targets for novel therapeutics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Better treatment of autoimmune diseases requires an improved understanding of the cellular and molecular mechanisms that lead to the breakdown of immune tolerance. The discovery of individuals with ...germline mutations in PIK3CD (which encodes the p110δ catalytic subunit of PI3K) has revealed the importance of regulated PI3Kδ activity to maintain tolerance. These patients display a range of symptoms including both immunodeficiency and autoimmunity. Here, we discuss recent advances in our understanding of how dysregulated PI3Kδ signaling affects the activation and differentiation of multiple cell types leading to the production of autoantibodies in these patients. This has lessons, not only for the treatment of these patients, but also for the potential role of dysregulated PI3Kδ in other patients with autoimmune conditions.
B helper follicular T (Tfh) cells are critical for long-term humoral immunity. However, it remains unclear how these cells are recruited and contribute to secondary immune responses. Here we show ...that primary Tfh cells segregate into follicular mantle (FM) and germinal center (GC) subpopulations that display distinct gene expression signatures. Restriction of the primary Tfh cell subpopulation in the GC was mediated by downregulation of chemotactic receptor EBI2. Following collapse of the GC, memory T cells persisted in the outer follicle where they scanned CD169+ subcapsular sinus macrophages. Reactivation and intrafollicular expansion of these follicular memory T cells in the subcapsular region was followed by their extrafollicular dissemination via the lymphatic flow. These data suggest that Tfh cells integrate their antigen-experience history to focus T cell help within the GC during primary responses but act rapidly to provide systemic T cell help after re-exposure to the antigen.
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•Primary Tfh cells are confined to the germinal center•Follicular memory T cells scan subcapsular sinus macrophages for antigen•Secondary Tfh cells are reactivated and proliferate in the subcapsular region•Secondary Tfh cells egress from the follicle via the subcapsular sinus
This study shows that Tfh cells are confined to the germinal center (GC) in the primary response and that follicular memory T cells are reactivated and proliferate in the subcapsular region. It also shows that Tfh cells are able to egress from the follicle in the secondary response.
Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphoinositide 3-kinase (PI3K), result in hyperactivation of the PI3K–AKT–mechanistic target of ...rapamycin pathway and underlie a novel inborn error of immunity. Affected subjects exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or cytomegalovirus infection, and increased incidence of B-cell lymphoproliferation, lymphoma, or both. Mechanisms underlying disease pathogenesis remain unknown.
Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in patients with PIK3CD GOF mutations, identify key molecules required for cell-mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this and other EBV-opathies.
We studied the consequences of PIK3CD GOF mutations on the generation, differentiation, and function of CD8+ T cells and natural killer (NK) cells, which are implicated in host defense against infection with herpesviruses, including EBV.
PIK3CD GOF total and EBV-specific CD8+ T cells were skewed toward an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion and increased susceptibility to reactivation-induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF mutations. NK cells in patients with PIK3CD GOF mutations also exhibited perturbed expression of differentiation-associated molecules. Both CD8+ T and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, programmed death ligand 1/2, and CD70.
PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8+ T and NK cells. These defects might contribute to clinical features of affected subjects, such as impaired immunity to herpesviruses and tumor surveillance.
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Interleukin-2 (IL-2) is an established therapeutic agent used for cancer immunotherapy. Since treatment efficacy is mediated by CD8
and NK cell activity at the tumour site, considerable efforts have ...focused on generating variants that expand these subsets systemically, as exemplified by IL-2/antibody complexes and 'superkines'. Here we describe a novel determinant of antitumour activity using fusion proteins consisting of IL-2 and the antibody fragment crystallizable (Fc) region. Generation of long-lived IL-2-Fc variants in which CD25 binding is abolished through mutation effectively prevents unwanted activation of CD25
regulatory T-cells (Tregs) and results in strong expansion of CD25
cytotoxic subsets. Surprisingly, however, such variants are less effective than wild-type IL-2-Fc in mediating tumour rejection. Instead, we report that efficacy is crucially dependent on depletion of Tregs through Fc-mediated immune effector functions. Our results underpin an unexpected mechanism of action and provide important guidance for the development of next generation IL-2 therapeutics.
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated downstream of many key cytokine receptors expressed by lymphocytes. As such, it plays a critical ...role in regulating B cells as well as CD4
and CD8
T cells. Patients with clinically significant immunodeficiency and immune dysregulation resulting from loss-of-function or gain-of-function mutations in STAT3 have been described. These individuals provide insight into the critical role of this transcription factor in the regulation of immune responses and the balance between effective immune protection and autoimmunity.
Gain-of-function (GOF) mutations in
, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune ...responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with
GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in
In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.
Cytokine-mediated intracellular signaling pathways are fundamental for the development, activation, and differentiation of lymphocytes. These distinct processes underlie protection against infectious ...diseases after natural infection with pathogens or immunization, thereby providing the host with long-lived immunological memory. In contrast, aberrant cytokine signaling can also result in conditions of immune dysregulation, such as early-onset autoimmunity. Thus, balanced signals provided by distinct cytokines, and delivered to specific cell subsets, are critical for immune homeostasis. The essential roles of cytokines in human immunity have been elegantly and repeatedly revealed by the discovery of individuals with mutations in cytokine ligands, receptors, and downstream transcription factors that cause primary immunodeficiency or autoimmune conditions. In this article, we review how the discovery and characterization of such individuals has identified nonredundant, and often highly specialized, functions of specific cytokines and immune cell subsets in human lymphocyte biology, host defense against infections, and immune regulation.
Introduction
Germline CARD11 gain-of-function (GOF) mutations cause B cell Expansion with NF-κB and T cell Anergy (BENTA) disease, whilst somatic GOF CARD11 mutations recur in diffuse large B cell ...lymphoma (DLBCL) and in up to 30% of the peripheral T cell lymphomas (PTCL) adult T cell leukemia/lymphoma (ATL), cutaneous T cell lymphoma (CTCL) and Sezary Syndrome. Despite their frequent acquisition by PTCL, the T cell-intrinsic effects of CARD11 GOF mutations are poorly understood.
Methods
Here, we studied B and T lymphocytes in mice with a germline Nethyl-N-nitrosourea (ENU)-induced Card11
M365K
mutation identical to a mutation identified in DLBCL and modifying a conserved region of the CARD11 coiled-coil domain recurrently mutated in DLBCL and PTCL.
Results and discussion
Our results demonstrate that CARD11.M365K is a GOF protein that increases B and T lymphocyte activation and proliferation following antigen receptor stimulation. Germline Card11
M365K
mutation was insufficient alone to cause B or T-lymphoma, but increased accumulation of germinal center (GC) B cells in unimmunized and immunized mice. Card11
M365K
mutation caused cell-intrinsic over-accumulation of activated T cells, T regulatory (T
REG
), T follicular (T
FH
) and T follicular regulatory (T
FR
) cells expressing increased levels of ICOS, CTLA-4 and PD-1 checkpoint molecules. Our results reveal CARD11 as an important, cell-autonomous positive regulator of T
FH
, T
REG
and T
FR
cells. They highlight T cell-intrinsic effects of a GOF mutation in the CARD11 gene, which is recurrently mutated in T cell malignancies that are often aggressive and associated with variable clinical outcomes.
Engagement of cytokine receptors by specific ligands activate Janus kinase-signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte ...behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21-induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.
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