Life Sciences Research for Lifelong Health

Publications michelle-linterman

Title / Authors / Details Open Access Download

Defective germinal center B-cell response and reduced arthritic pathology in microRNA-29a-deficient mice.
van Nieuwenhuijze A, Dooley J, Humblet-Baron S, Sreenivasan J, Koenders M, Schlenner SM, Linterman M, Liston A

MicroRNA (miR) are short non-coding RNA sequences of 19-24 nucleotides that regulate gene expression by binding to mRNA target sequences. The miR-29 family of miR (miR-29a, b-1, b-2 and c) is a key player in T-cell differentiation and effector function, with deficiency causing thymic involution and a more inflammatory T-cell profile. However, the relative roles of different miR-29 family members in these processes have not been dissected. We studied the immunological role of the individual members of the miR-29 family using mice deficient for miR-29a/b-1 or miR-29b-2/c in homeostasis and during collagen-induced arthritis. We found a definitive hierarchy of immunological function, with the strong phenotype of miR-29a-deficiency in thymic involution and T-cell activation being reduced or absent in miR-29c-deficient mice. Strikingly, despite elevating the Th1 and Th17 responses, loss of miR-29a conferred near-complete protection from collagen-induced arthritis (CIA), with profound defects in B-cell proliferation and antibody production. Our results identify the hierarchical structure of the miR-29 family in T-cell biology, and identify miR-29a in B cells as a potential therapeutic target in arthritis.

+ View Abstract

Cellular and molecular life sciences : CMLS, , 1420-9071, , 2017

PMID: 28124096

Shaping Variation in the Human Immune System.
Liston A, Carr EJ, Linterman MA

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.

+ View Abstract

Trends in immunology, , 1471-4981, , 2016

PMID: 27693120

Can follicular helper T cells be targeted to improve vaccine efficacy?
Linterman MA, Hill DL

The success of most vaccines relies on the generation of antibodies to provide protection against subsequent infection; this in turn depends on a robust germinal centre (GC) response that culminates in the production of long-lived antibody-secreting plasma cells. The size and quality of the GC response are directed by a specialised subset of CD4 (+) T cells: T follicular helper (Tfh) cells. Tfh cells provide growth and differentiation signals to GC B cells and mediate positive selection of high-affinity B cell clones in the GC, thereby determining which B cells exit the GC as plasma cells and memory B cells. Because of their central role in the production of long-lasting humoral immunity, Tfh cells represent an interesting target for rational vaccine design.

+ View Abstract

F1000Research, 5, 2046-1402, , 2016

PMID: 26989476

Open Access

Follicular Helper T Cells.
Vinuesa CG, Linterman MA, Yu D, MacLennan IC

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 RNAbinding 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, 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. Expected final online publication date for the Annual Review of Immunology Volume 34 is May 20, 2016. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

+ View Abstract

Annual review of immunology, , 1545-3278, , 2016

PMID: 26907215

The cellular composition of the human immune system is shaped by age and cohabitation.
Carr EJ, Dooley J, Garcia-Perez JE, Lagou V, Lee JC, Wouters C, Meyts I, Goris A, Boeckxstaens G, Linterman MA, Liston A

Detailed population-level description of the human immune system has recently become achievable. We used a 'systems-level' approach to establish a resource of cellular immune profiles of 670 healthy individuals. We report a high level of interindividual variation, with low longitudinal variation, at the level of cellular subset composition of the immune system. Despite the profound effects of antigen exposure on individual antigen-specific clones, the cellular subset structure proved highly elastic, with transient vaccination-induced changes followed by a return to the individual's unique baseline. Notably, the largest influence on immunological variation identified was cohabitation, with 50% less immunological variation between individuals who share an environment (as parents) than between people in the wider population. These results identify local environmental conditions as a key factor in shaping the human immune system.

+ View Abstract

Nature immunology, , 1529-2916, , 2016

PMID: 26878114

Follicular regulatory T cells can be specific for the immunizing antigen and derive from naive T cells.
Aloulou M, Carr EJ, Gador M, Bignon A, Liblau RS, Fazilleau N, Linterman MA

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.

+ View Abstract

Nature communications, 7, 2041-1723, 10579, 2016

PMID: 26818004

Open Access

Premature thymic involution is independent of structural plasticity of the thymic stroma.
Franckaert D, Schlenner SM, Heirman N, Gill J, Skogberg G, Ekwall O, Put K, Linterman MA, Dooley J, Liston A

The thymus is the organ devoted to T-cell production. The thymus undergoes multiple rounds of atrophy and redevelopment before degenerating with age in a process known as involution. This process is poorly understood, despite the influence the phenomenon has on peripheral T-cell numbers. Here we have investigated the FVB/N mouse strain, which displays premature thymic involution. We find multiple architectural and cellular features that precede thymic involution, including disruption of the epithelial-endothelial relationship and a progressive loss of pro-T cells. The architectural features, reminiscent of the human thymus, are intrinsic to the non-hematopoietic compartment and are neither necessary nor sufficient for thymic involution. By contrast, the loss of pro-T cells is intrinsic to the hematopoietic compartment, and is sufficient to drive premature involution. These results identify pro-T-cell loss as the main driver of premature thymic involution, and highlight the plasticity of the thymic stroma, capable of maintaining function across diverse inter-strain architectures. This article is protected by copyright. All rights reserved.

+ View Abstract

European journal of immunology, , 1521-4141, , 2015

PMID: 25627671

Regulatory T cells and control of the germinal centre response.
Vanderleyden I, Linterman MA, Smith KG

Germinal centres (GCs) are specialised lymphoid microenvironments that form in secondary B-cell follicles upon exposure to T-dependent antigens. In the GC, clonal expansion, selection and differentiation of GC B cells result in the production of high-affinity plasma cells and memory B cells that provide protection against subsequent infection. The GC is carefully regulated to fulfil its critical role in defence against infection and to ensure that immunological tolerance is not broken in the process. The GC response can be controlled by a number of mechanisms, one of which is by forkhead box p3 expressing regulatory T (Treg) cells, a suppressive population of CD4+ T cells. A specialised subset of Treg cells - follicular regulatory T (Tfr) cells - form after immunisation and are able to access the GC, where they control the size and output of the response. Our knowledge of Treg cell control of the GC is expanding. In this review we will discuss recent advances in the field, with a particular emphasis on the differentiation and function of Tfr cells in the GC.

+ View Abstract

Arthritis research & therapy, 16, 1478-6362, 471, 2014

PMID: 25606598

Open Access

Promiscuous Foxp3-cre activity reveals a differential requirement for CD28 in Foxp3(+) and Foxp3(-) T cells.
Franckaert D, Dooley J, Roos E, Floess S, Huehn J, Luche H, Fehling HJ, Liston A, Linterman MA, Schlenner SM

Costimulatory signals by CD28 are critical for thymic regulatory T-cell (Treg) development. To determine the functional relevance of CD28 for peripheral Treg post thymic selection, we crossed the widely used Forkhead box protein 3 (Foxp3)-CreYFP mice to mice bearing a conditional Cd28 allele. Treg-specific CD28 deficiency provoked a severe autoimmune syndrome as a result of a strong disadvantage in competitive fitness and proliferation of CD28-deficient Tregs. By contrast, Treg survival and lineage integrity were not affected by the lack of CD28. This data demonstrate that, even after the initial induction requirement, Treg maintain a higher dependency on CD28 signalling than conventional T cells for homeostasis. In addition, we found the Foxp3-CreYFP allele to be a hypomorph, with reduced Foxp3 protein levels. Furthermore, we report here the stochastic activity of the Foxp3-CreYFP allele in non-Tregs, sufficient to recombine some conditional alleles (including Cd28) but not others (including R26-RFP). This hypomorphism and 'leaky' expression of the Foxp3-CreYFP allele should be considered when analysing the conditionally mutated Treg.Immunology and Cell Biology advance online publication, 23 December 2014; doi:10.1038/icb.2014.108.

+ View Abstract

Immunology and cell biology, , 1440-1711, , 2014

PMID: 25533288

Open Access

Treg cells and CTLA-4: the ball and chain of the germinal center response.
Linterman MA, Denton AE

The mechanism by which regulatory T cells control the germinal center response is unknown. In this issue of Immunity, Wing et al. (2014) and Sage et al. (2014) demonstrate that CTLA-4 is a critical effector molecule used by regulatory T cells to control the germinal center.

+ View Abstract

Immunity, 41, 1097-4180, 876-8, 2014

PMID: 25526300

CD28 expression is required after T cell priming for helper T cell responses and protective immunity to infection.
Linterman MA,Denton AE,Divekar DP,Zvetkova I,Kane L,Ferreira C,Veldhoen M,Clare S,Dougan G,Espeli M,Smith KG

The co-stimulatory molecule CD28 is essential for activation of helper T cells. Despite this critical role, it is not known whether CD28 has functions in maintaining T cell responses following activation. To determine the role for CD28 after T cell priming, we generated a strain of mice where CD28 is removed from CD4(+) T cells after priming. We show that continued CD28 expression is important for effector CD4(+) T cells following infection; maintained CD28 is required for the expansion of T helper type 1 cells, and for the differentiation and maintenance of T follicular helper cells during viral infection. Persistent CD28 is also required for clearance of the bacterium Citrobacter rodentium from the gastrointestinal tract. Together, this study demonstrates that CD28 persistence is required for helper T cell polarization in response to infection, describing a novel function for CD28 that is distinct from its role in T cell priming.

+ View Abstract

eLife, 3, 2050-084X, , 2014

PMID: 25347065

Open Access

Cellular Plasticity of CD4+ T Cells in the Intestine.
V Brucklacher-Waldert, EJ Carr, MA Linterman, M Veldhoen

Barrier sites such as the gastrointestinal tract are in constant contact with the environment, which contains both beneficial and harmful components. The immune system at the epithelia must make the distinction between these components to balance tolerance, protection, and immunopathology. This is achieved via multifaceted immune recognition, highly organized lymphoid structures, and the interaction of many types of immune cells. The adaptive immune response in the gut is orchestrated by CD4(+) helper T (Th) cells, which are integral to gut immunity. In recent years, it has become apparent that the functional identity of these Th cells is not as fixed as initially thought. Plasticity in differentiated T cell subsets has now been firmly established, in both health and disease. The gut, in particular, utilizes CD4(+) T cell plasticity to mold CD4(+) T cell phenotypes to maintain its finely poised balance of tolerance and inflammation and to encourage biodiversity within the enteric microbiome. In this review, we will discuss intestinal helper T cell plasticity and our current understanding of its mechanisms, including our growing knowledge of an evolutionarily ancient symbiosis between microbiota and malleable CD4(+) T cell effectors.

+ View Abstract

Frontiers in immunology, 5, 1664-3224, 488, 2014

PMID: 25339956

Open Access

Human T-follicular helper and T-follicular regulatory cell maintenance is independent of germinal centers.
Wallin EF, Jolly EC, Suchánek O, Bradley JA, Espéli M, Jayne DR, Linterman MA, Smith KG

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.

+ View Abstract

Blood, 124, 1528-0020, 2666-74, 2014

PMID: 25224411

Open Access

Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8+ T cells.
Denton AE, Roberts EW, Linterman MA, Fearon DT

Fibroblastic reticular cells (FRCs), through their expression of CC chemokine ligand (CCL)19 and CCL21, attract and retain T cells in lymph nodes (LNs), but whether this function applies to both resting and activated T cells has not been examined. Here we describe a model for conditionally depleting FRCs from LNs based on their expression of the diphtheria toxin receptor (DTR) directed by the gene encoding fibroblast activation protein-α (FAP). As expected, depleting FAP(+) FRCs causes the loss of naïve T cells, B cells, and dendritic cells from LNs, and this loss decreases the magnitude of the B- and T-cell responses to a subsequent infection with influenza A virus. In contrast, depleting FAP(+) FRCs during an ongoing influenza infection does not diminish the number or continued response of activated T and B cells in the draining LNs, despite still resulting in the loss of naïve T cells. Therefore, different rules govern the LN trafficking of resting and activated T cells; once a T cell is engaged in antigen-specific clonal expansion, its retention no longer depends on FRCs or their chemokines, CCL19 and CCL21. Our findings suggest that activated T cells remain in the LN because they down-regulate the expression of the sphingosine-1 phosphate receptor-1, which mediates the exit of lymphocytes from secondary lymphoid organs. Therefore, LN retention of naïve lymphocytes and the initiation of an immune response depend on FRCs, but is an FRC independent and possibly cell-autonomous response of activated T cells, which allows the magnitude of clonal expansion to determine LN egress.

+ View Abstract

Proceedings of the National Academy of Sciences of the United States of America, 111, 1091-6490, 12139-44, 2014

PMID: 25092322

Open Access

How T follicular helper cells and the germinal centre response change with age.
Linterman MA

Normal ageing is accompanied by a decline in the function of the immune system that causes an increased susceptibility to infections and an impaired response to vaccination in older individuals. This results in an increased disease burden in the aged population, even with good immunisation programmes in place. The decreased response to vaccination is partly due to the diminution of the germinal centre response with age, caused by impaired T-cell help to B cells. Within the germinal centre, T-cell help is provided by a specialised subset of CD4(+) T cells; T follicular helper (Tfh) cells. Tfh cells provide survival and selection signals to germinal centre B cells, allowing them to egress from the germinal centre and become long-live plasma cells or memory B cells, and provide life-long protection against subsequent infection. This review will discuss the cellular and molecular changes in both Tfh cells and germinal centre B cells that occur with advancing age, which result in a smaller germinal centre response and a less effective response to immunisation.

+ View Abstract

Immunology and cell biology, 92, 1440-1711, 72-9, 2014

PMID: 24217812

Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway.
Lee JC, Espéli M, Anderson CA, Linterman MA, Pocock JM, Williams NJ, Roberts R, Viatte S, Fu B, Peshu N, Hien TT, Phu NH, Wesley E, Edwards C, Ahmad T, Mansfield JC, Gearry R, Dunstan S, Williams TN, Barton A, Vinuesa CG, , Parkes M, Lyons PA, Smith KG

The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a patient's life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFβ1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses.

+ View Abstract

Cell, 155, 1097-4172, 57-69, 2013

PMID: 24035192

Open Access

MicroRNA regulation of T-cell development.
Dooley J, Linterman MA, Liston A

MicroRNAs are short, 19-24 nucleotide long, RNA molecules capable of regulating the longevity and, to a lesser extent, translation of messenger RNA (mRNA) species. The function of the microRNA network, and indeed, even that of individual microRNA species, can have profoundly different roles in even a single cell type as the microRNA/mRNA composition evolves. As the role of microRNA within T cells has come under increasing scrutiny, several distinct checkpoints have been demonstrated to have a particular reliance on microRNA regulation. MicroRNAs are arguably most important in T cells during the earliest and last stages in T-cell biology. The first stages of early thymic differentiation have a crucial reliance on the microRNA network, while later stages and peripheral homeostasis are largely, although not completely, microRNA-independent. The most profound effects on T cells are in the activation of effector and regulatory functions of conventional and regulatory T cells, where microRNA deficiency results in a near-complete loss of function. In this review, we focus on integrating the research on individual microRNA into a more global understanding of the function of the microRNA regulatory network in T cells.

+ View Abstract

Immunological reviews, 253, 1600-065X, 53-64, 2013

PMID: 23550638

T-follicular helper cell differentiation and the co-option of this pathway by non-helper cells.
Linterman MA, Liston A, Vinuesa CG

Human and mouse studies performed over the last decade have established that follicular helper T (Tfh) cells are a CD4(+) helper subset specialized in the provision of help to B cells. Tfh differentiation is driven by expression of the transcriptional repressor B-cell lymphoma-6 (Bcl-6), which turns on a program that guides T cells close to B-cell areas where Tfh cells first provide help to B cells. Sustained Bcl-6 expression promotes the entry of Tfh cells into follicles and modulates their cytokine expression profile so they can support and select germinal center B cells that have acquired affinity-enhancing mutations in their immunoglobulin genes. Forkhead box 3 protein (Foxp3)(+) regulatory T cells and invariant natural killer T (NKT) cells can also co-opt the Bcl-6-dependent follicular differentiation pathway to migrate into B-cell follicles and regulate antibody responses. The resulting NKT follicular helper cells drive a distinctive type of T-dependent B-cell response to lipid-containing antigens, whereas FoxP3(+) follicular regulatory (Tfr) cells exert a suppressive function on germinal centers. Elucidating how Tfr cells are functionally and numerically regulated and the factors that control the balance between Tfh and Tfr cells is likely to be critical for improved understanding of the pathogenesis and progression of autoimmunity and lymphomas of germinal center origin, and generation of effective vaccines.

+ View Abstract

Immunological reviews, 247, 1600-065X, 143-59, 2012

PMID: 22500838

The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-α receptor.
Papadopoulou AS, Dooley J, Linterman MA, Pierson W, Ucar O, Kyewski B, Zuklys S, Hollander GA, Matthys P, Gray DH, De Strooper B, Liston A

Thymic output is a dynamic process, with high activity at birth punctuated by transient periods of involution during infection. Interferon-α (IFN-α) is a critical molecular mediator of pathogen-induced thymic involution, yet despite the importance of thymic involution, relatively little is known about the molecular integrators that establish sensitivity. Here we found that the microRNA network dependent on the endoribonuclease Dicer, and specifically microRNA miR-29a, was critical for diminishing the sensitivity of the thymic epithelium to simulated infection signals, protecting the thymus against inappropriate involution. In the absence of Dicer or the miR-29a cluster in the thymic epithelium, expression of the IFN-α receptor by the thymic epithelium was higher, which allowed suboptimal signals to trigger rapid loss of thymic cellularity.

+ View Abstract

Nature immunology, 13, 1529-2916, 181-7, 2012

PMID: 22179202

Open Access

Foxp3+ follicular regulatory T cells control the germinal center response.
Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, Srivastava M, Divekar DP, Beaton L, Hogan JJ, Fagarasan S, Liston A, Smith KG, Vinuesa CG

Follicular helper (T(FH)) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of T(FH) numbers maintains self tolerance. We describe a population of Foxp3(+)Blimp-1(+)CD4(+) T cells constituting 10-25% of the CXCR5(high)PD-1(high)CD4(+) T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (T(FR)) cells share phenotypic characteristics with T(FH) and conventional Foxp3(+) regulatory T (T(reg)) cells yet are distinct from both. Similar to T(FH) cells, T(FR) cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, T(FR) cells originate from thymic-derived Foxp3(+) precursors, not naive or T(FH) cells. T(FR) cells are suppressive in vitro and limit T(FH) cell and germinal center B cell numbers in vivo. In the absence of T(FR) cells, an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the T(FH) differentiation pathway is co-opted by T(reg) cells to control the germinal center response.

+ View Abstract

Nature medicine, 17, 1546-170X, 975-82, 2011

PMID: 21785433

Open Access

T follicular helper cells during immunity and tolerance.
Linterman MA, Vinuesa CG

Helper T cells are required for the generation of a potent immune response to foreign antigens. Amongst them, T follicular helper (Tfh) cells are specialized in promoting protective, long-lived antibody responses that arise from germinal centers. Within these structures, the specificity of B cell receptors may change, due to the process of random somatic hypermutation aimed at increasing the overall affinity of the antibody response. The danger of emerging self-reactive specificities is offset by a stringent selection mechanism delegated in great part to Tfh cells. Only those B cells receiving survival signals from Tfh cells can exit the germinal centers to join the long-lived pools of memory B cells and bone marrow-homing plasma cells. Thus, a crucial immune tolerance checkpoint to prevent long-term autoantibody production lies in the ability to tolerize Tfh cells and to control positive and negative selection signals delivered by this subset. This review tackles the known mechanisms that ensure Tfh tolerance, many of them shared by other T helper subsets during thymic development and priming, but others unique to Tfh cells. Amongst the latter are checkpoints at the stages of Tfh differentiation, follicular migration, growth, longevity, and quality control of selection signals. Finally, we also discuss the consequences of a breakdown in Tfh tolerance.

+ View Abstract

Progress in molecular biology and translational science, 92, 1877-1173, 207-48, 2010

PMID: 20800823

T cells and follicular dendritic cells in germinal center B-cell formation and selection.
Vinuesa CG, Linterman MA, Goodnow CC, Randall KL

Germinal centers (GCs) are specialized microenvironments formed after infection where activated B cells can mutate their B-cell receptors to undergo affinity maturation. A stringent process of selection allows high affinity, non-self-reactive B cells to become long-lived memory B cells and plasma cells. While the precise mechanism of selection is still poorly understood, the last decade has advanced our understanding of the role of T cells and follicular dendritic cells (FDCs) in GC B-cell formation and selection. T cells and non-T-cell-derived CD40 ligands on FDCs are essential for T-dependent (TD) and T-independent GC formation, respectively. TD-GC formation requires Bcl-6-expressing T cells capable of signaling through SAP, which promotes formation of stable T:B conjugates. By contrast, differentiation of B blasts along the extrafollicular pathway is less dependent on SAP. T-follicular helper (Tfh) cell-derived CD40L, interleukin-21, and interleukin-4 play important roles in GC B-cell proliferation, survival, and affinity maturation. A role for FDC-derived integrin signals has also emerged: GC B cells capable of forming an immune synapse with FDCs have a survival advantage. This emerges as a powerful mechanism to ensure death of B cells that bind self-reactive antigen, which would not normally be presented on FDCs.

+ View Abstract

Immunological reviews, 237, 1600-065X, 72-89, 2010

PMID: 20727030

MicroRNA in the adaptive immune system, in sickness and in health.
Liston A, Linterman M, Lu LF

MicroRNA are emerging as key regulators of the development and function of adaptive immunity. These 19-24 nucleotide regulatory RNA molecules have essential roles in multiple faucets of adaptive immunity, from regulating the development of the key cellular players to the activation and function in immune responses.

+ View Abstract

Journal of clinical immunology, 30, 1573-2592, 339-46, 2010

PMID: 20191314

IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses.
Linterman MA, Beaton L, Yu D, Ramiscal RR, Srivastava M, Hogan JJ, Verma NK, Smyth MJ, Rigby RJ, Vinuesa CG

During T cell-dependent responses, B cells can either differentiate extrafollicularly into short-lived plasma cells or enter follicles to form germinal centers (GCs). Interactions with T follicular helper (Tfh) cells are required for GC formation and for selection of somatically mutated GC B cells. Interleukin (IL)-21 has been reported to play a role in Tfh cell formation and in B cell growth, survival, and isotype switching. To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells. We show that IL-21 acts in a B cell-intrinsic fashion to control GC B cell formation. Mixed bone marrow chimeras identified a significant B cell-autonomous effect of IL-21 receptor (R) signaling throughout all stages of the GC response. IL-21 deficiency profoundly impaired affinity maturation and reduced the proportion of IgG1(+) GC B cells but did not affect formation of early memory B cells. IL-21R was required on GC B cells for maximal expression of Bcl-6. In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21.

+ View Abstract

The Journal of experimental medicine, 207, 1540-9538, 353-63, 2010

PMID: 20142429

Open Access

Signals that influence T follicular helper cell differentiation and function.
Linterman MA, Vinuesa CG

Follicular helper T cells have recently emerged as a separate CD4(+) T helper lineage specialised in provision of help to B cells. They develop independently from Th1, Th2 and Th17 cells and are critical for humoral immunity, including the generation of long-lived and high affinity plasma cells and memory cells crucial for long-term protection against infections. A stepwise differentiation programme has emerged in which T cell receptor (TCR) signalling strength, CD28-mediated costimulation, B cell-derived inducible costimulator ligand signals, induction of c-maf and actions of cytokines, including interleukin (IL)-6 and IL-21, lead to upregulation of the transcriptional repressor B cell lymphoma 6 (Bcl-6) that drives T follicular helper (Tfh) cell differentiation. Bcl-6 turns on a repression programme that targets Blimp-1, transcriptional regulators of other helper lineages and microRNAs. Their concerted actions modulate expression of chemokine receptors, surface molecules and cytokines critical for follicular homing and B cell helper functions. Here, we review the nature of Tfh cells providing help to B cells during the two phases of B cell activation that occur in the outer T zone and, for some B cells, in germinal centres (GC). Recent insights into the signalling events that drive terminal differentiation of Tfh cells critical for selecting somatically mutated GC B cells and the consequences of Tfh dysregulation for immunodeficiency and autoimmune pathology are discussed.

+ View Abstract

Seminars in immunopathology, 32, 1863-2300, 183-96, 2010

PMID: 20107805