Nodal T-cell lymphomas with a T-follicular helper cell phenotype

The discovery and characterisation of T-follicular helper (TFH) cells, a distinct functional subset of T-helper cells has led to the recognition that some peripheral T-cell lymphomas (PTCLs) have a TFH cell immunophenotype. Due to the overlap in clinical, morphological, immunophenotypic and genetic characteristics, the revised 4^th edition to the WHO classification recognises one umbrella category of ‘angioimmunoblastic T-cell lymphoma and other nodal TCLs of TFH cell origin’. This review provides a brief overview of TFH cells with special emphasis on function and phenotype and a more detailed discussion of clinical, morphologic, immunophenotypic and genotypic characteristics of AITL, follicular T-cell lymphoma and nodal PTCL with TFH phenotype which constitute nodal TCLs of TFH origin. Secondary B-cell proliferations (often EBV positive) and features that help differentiate reactive lymphoid hyperplasia and other types of lymphoma, including PTCL, NOS and secondary B-cell lymphomas and classic Hodgkin lymphoma, from nodal TCLs with a TFH phenotype are discussed.     

T cells and follicular dendritic cells in germinal center B-cell formation and selection

Summary: 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.     

T follicular helper cell heterogeneity: Time,space, and function

T follicular helper (Tfh) cells play a crucial role in orchestrating the humoral arm of adaptive immune responses. Mature Tfh cells localize to follicles in secondary lymphoid organs (SLOs) where they provide help to B cells in germinal centers (GCs) to facilitate immunoglobulin affinity maturation, class‐switch recombination, and generation of long‐lived plasma cells and memory B cells. Beyond the canonical GC Tfh cells, it has been increasingly appreciated that the Tfh phenotype is highly diverse and dynamic. As naive CD4⁺ T cells progressively differentiate into Tfh cells, they migrate through a variety of microanatomical locations to obtain signals from other cell types, which in turn alters their phenotypic and functional profiles. We herein review the heterogeneity of Tfh cells marked by the dynamic phenotypic changes accompanying their developmental program. Focusing on the various locations where Tfh and Tfh‐like cells are found, we highlight their diverse states of differentiation. Recognition of Tfh cell heterogeneity has important implications for understanding the nature of T helper cell identity specification, especially the plasticity of the Tfh cells and their ontogeny as related to conventional T helper subsets.     

Aire deficient dendritic cells promote the T follicular helper cells differentiation

Autoimmune regulator (Aire), primarily expressed in medullary thymic epithelial cells (mTECs), maintains central immune tolerance through the clearance of self-reactive T cells. Aire can also be expressed in dendritic cells (DCs), and DCs can mediate T follicular helper (T_FH) cell differentiation and self-reactive B cell activation through inducible costimulator molecule ligand (ICOSL) and interleukin 6 (IL-6), which can cause autoimmune diseases. To confirm whether Aire in DCs affects T_FH cell differentiation and to determine the role of Aire in the maintenance of peripheral immune tolerance, this study observed the effects of Aire deficiency on T_FH cells using Aire knockout mice. The results showed that Aire deficiency caused increased number of T_FH cells, both in vivo and in vitro. Further studies showed that Aire deficiency promoted T_FH differentiation through the upregulation of ICOSL and IL-6 in DCs. Thus Aire could suppress the expression of ICOSL and IL-6 to inhibit T_FH cell differentiation.     

T cell-expressed microRNAs critically regulate germinal center T follicular helper cell function and maintenance in acute viral infection in mice

Constitutive T cell-intrinsic miRNA expression is required for the differentiation of naïve CD4⁺ T cells into Tfh cells, thus making it difficult to study the role of miRNAs in the maintenance of already established Tfh cells and ongoing germinal center (GC) responses. To overcome this problem, we here used temporally controlled ablation of mature miRNAs specifically in CD4⁺ T cells during acute LCMV infection in mice. T cell-intrinsic miRNA expression was not only critical at early stages of Tfh cell differentiation, but also important for the maintenance of already established Tfh cells. In addition, CD4⁺ T cell-specific ablation of miRNAs resulted in impaired GC B cell responses. Notably, miRNA deficiency also compromised the antigen-specific CD4⁺ T cell compartment, Th1 cells, Treg cells, and Tfr cells. In conclusion, our results highlight miRNAs as important regulators of Tfh cells, thus providing novel insights into the molecular events that govern T cell–B cell interactions and Th cell identity.     

Plasma cell differentiation during the germinal center reaction

Germinal centers (GCs) are formed in secondary lymphoid tissues upon immunization with T‐dependent antigens. In GCs, somatic hypermutation generates B cells with increased antibody affinity and these high‐affinity B cells preferentially differentiate into plasma cells, which home to bone marrow and confer long‐lived humoral immunity. Recent studies have shed new light on the cellular and molecular basis for initiating the transition from a GC B cell to a plasma cell. Here, we review recent progress in our understanding of how plasma cell generation during the GC reaction is regulated for inducing effective long‐term protective immunity and for preventing harmful autoimmunity.     

Natural killer T-cell characterization through gene expression profiling: an account of versatility bridging T helper type 1 (Th1), Th2 and Th17 immune responses

Natural killer T (NKT) cells constitute a distinct lymphocyte lineage at the interface between innate and adaptive immunity, yet their role in the immune response remains elusive. Whilst NKT cells share features with other conventional T lymphocytes, they are unique in their rapid, concomitant production of T helper type 1 (Th1) and Th2 cytokines upon T-cell receptor (TCR) ligation. In order to characterize the gene expression of NKT cells, we performed comparative microarray analyses of murine resting NKT cells, natural killer (NK) cells and naïve conventional CD4⁺ T helper (Th) and regulatory T cells (Treg). We then compared the gene expression profiles of resting and alpha-galactosylceramide (αGalCer)-activated NKT cells to elucidate the gene expression signature upon activation. We describe here profound differences in gene expression among the various cell types and the identification of a unique NKT cell gene expression profile. In addition to known NKT cell-specific markers, many genes were expressed in NKT cells that had not been attributed to this population before. NKT cells share features not only with Th1 and Th2 cells but also with Th17 cells. Our data provide new insights into the functional competence of NKT cells which will facilitate a better understanding of their versatile role during immune responses.     

滤泡辅助性T细胞与相关疾病研究进展

滤泡辅助性T细胞(Tfh)是近几年发现的一种新的T细胞亚群,与Th1细胞、Th2细胞、Th17细胞及调节性T细胞(Tr)相互促进或拮抗,维持免疫系统的正常生理功能,其主要功能是辅助B细胞分化、发育和促进体液免疫应答,当Tfh细胞数量或功能紊乱时可引起自身免疫病、免疫缺陷病、肿瘤或感染性疾病的发生或加重.     

B cell helper T cells and type 1 diabetes

Type 1 diabetes is an autoimmune disease typically starting in childhood that culminates in the destruction of insulin-producing beta cells in the pancreas. Although type 1 diabetes is considered to be a primarily T cell–mediated disease, B cells clearly participate in the autoimmune process, as autoantibodies recognizing pancreatic islet antigen commonly appear in circulation before the onset of the disease. T cells providing helper functions to B cells have recently been shown to be involved in the pathogenesis of a wide range of antibody-associated immune disorders. These T cells include CXCR5-positive follicular T helper (Tfh) cells, and a recently described closely related CXCR5-negative subset coined peripheral T helper (Tph) cells. Here, we review the current state of knowledge on different B cell helper T cell subsets, focusing on their potential involvement in the development of type 1 diabetes.     

From SAP-less T cells to helpless B cells and back: dynamic T-B cell interactions underlie germinal center development and function

Operation of the immune system critically depends on intercellular communication among multiple cell types, frequently in the form of physical cell-cell interactions. Germinal centers (GCs) are highly organized tissue microdomains in which high affinity, class-switched, antibody-producing cells and humoral immune memory are generated. Critical underlying cell-cell interaction events include at the minimum binary interactions between CD4(+) T-helper cells and antigen-presenting dendritic cells (DCs), which ensure proper T-cell activation and acquisition of effecter potentials, and those between T-helper cells and antigen-activated B cells whereby the latter cells receive helper signals (e.g. CD40L) important for their proliferation, survival, and differentiation. How these critical cellular interaction events are molecularly regulated and dynamically orchestrated to support GC formation and function is still a study in progress. Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) has recently been defined as a pivotal molecule that controls cognate T-B interactions and GC formation. Detailed analysis of interaction and migration dynamics of SAP-deficient T cells has raised the interesting possibility that T cell:antigen-presenting cell interactions underlying GC development and function are regulated in a cell type- and spatiotemporal stage-specific manner. This has important implications for our understanding of synapse formation, helper signal delivery to B cells, follicular helper T-cell differentiation, and quality control of the GC reaction in general. A model of selective T-B interactions involving bi-directional feedback and feed-forward logic is proposed to underlie GC development and function.     

The emerging role of T follicular helper (TFH) cells in aging: Influence on the immune frailty

The world population is undergoing a rapid expansion of older adults. Aging is associated with numerous changes that affect all organs and systems, including every component of the immune system. Immunosenescence is a multifaceted process characterized by poor response to vaccine and higher incidence of bacterial and viral infections, cancer, cardiovascular and autoimmune diseases. Immunosenescence has been associated with chronic low-grade inflammation referred to as inflammaging, whose underlying mechanisms remain incompletely elucidated, including age-related changes affecting components of the innate and adaptive immune system. T follicular helper (T_FH) cells, present in lymphoid organs and in peripheral blood, are specialized in providing cognate help to B cells and are required for the production of immunoglobulins. Several subsets of T_FH cells have been identified in humans and mice and modifications in T_FH cell phenotype and function progressively occur with age. Dysfunctional T_FH cells play a role in cancer, autoimmune and cardiovascular diseases, all conditions particularly prevalent in elderly subjects. A specialized population of Treg cells, named T follicular regulatory (T_FR) cells, present in lymphoid organs and in peripheral blood, exerts opposing roles to T_FH cells in regulating immunity. Indeed, changes in T_FH/T_FR cell ratio constitute a relevant feature of aging. Herein we discuss the cellular and molecular changes in both T_FH cells and T_FR cells that occur in aging and recent findings suggesting that T_FH cells and/or their subsets could be involved in atherosclerosis, cancer, and autoimmunity.     

Shared and distinct roles of T peripheral helper and T follicular helper cells in human diseases

The interactions of CD4⁺ T cells and B cells are fundamental for the generation of protective antibody responses, as well as for the development of harmful autoimmune diseases. Recent studies of human tissues and blood samples have established a new subset of CD4⁺ B helper T cells named peripheral helper T (Tph) cells. Unlike T follicular helper (Tfh) cells, which interact with B cells within lymphoid organs, Tph cells provide help to B cells within inflamed tissues. Tph cells share many B helper-associated functions with Tfh cells and induce B cell differentiation toward antibody-producing cells. The differentiation mechanism is also partly shared between Tph and Tfh cells in humans, and both Tfh and Tph cells can be found within the same tissues, including cancer tissues. However, Tph cells display features distinct from those of Tfh cells, such as the expression of chemokine receptors associated with Tph cell localization within inflamed tissues and a low Bcl-6/Blimp1 ratio. Unlike that of Tfh cells, current evidence shows that the target of Tph cells is limited to memory B cells. In this review, we first summarize recent findings on human Tph cells and discuss how Tph and Tfh cells play shared and distinct roles in human diseases.     

T cell help to B cells: Cognate and atypical interactions in peripheral and intestinal lymphoid tissues

Enduring immunity against harmful pathogens depends on the generation of immunological memory. Serum immunoglobulins are constantly secreted by long-lived antibody-producing cells, which provide extended protection from recurrent exposures. These cells originate mainly from germinal center structures, wherein B cells introduce mutations to their immunoglobulin genes followed by affinity-based selection. Generation of high-affinity antibodies relies on physical contacts between T and B cells, a process that facilitates the delivery of fate decision signals. T-B cellular engagements are mediated through interactions between the T cell receptor and its cognate peptide presented on B cell major histocompatibility class II molecules. Here, we describe the cellular and molecular aspects of these cognate T-B interactions, and highlight exceptional cases, especially those arising at intestinal lymphoid organs, at which T cells provide help to B cells in an atypical manner, independent of T cell specificity.     

Human germinal center T cells are unique Th cells with high propensity for apoptosis induction

Collaborative interactions between T(h) cells and B cells are necessary for the production of antibody responses to most protein antigens and for the generation of memory B cells in germinal centers (GCs). Although it is well established that T(h) cells are pivotal for the GC reaction, the mechanisms that control the homeostasis of T(h) cells during the GC response remain largely unknown. Here we show that, unlike other effector T cells, a significant number of CD4(+)CD45RO(+)CD57(+) T cells, which are the major T(h) cells residing in the GCs, are undergoing apoptosis in vivo. CD4(+)CD45RO(+)CD57(+) GC T cells exhibit similar sensitivities to apoptotic signals and to caspase inhibitors as immature thymocytes. Moreover, CD4(+)CD45RO(+)CD57(+) GC T cells express a unique profile of genes that control apoptosis and cell cycle, providing possible molecular mechanisms for the high rates of apoptotic death of these T(h) cells in the GCs.