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Interleukin‐9 (IL‐9) producing CD4+ Th9 cells are a unique subset of effector cells involved in both health and disease. Th9 cells have been associated with protective immunity during parasitic infections with helminths, protozoans and extracellular pathogens, but implicated in disease states such as allergic asthma, atopic dermatitis, food allergy and autoimmune conditions including multiple sclerosis and ulcerative colitis. Here, we review the cytokine signaling pathways and downstream transcription factors required for IL‐9 expression and how human primary immunodeficiencies caused by monogenic mutations can help elucidate the complex requirements for human Th9 cell differentiation. Primary immunodeficiencies are a platform for investigating IL‐9 expression in primary human lymphocytes and by inference whether Th9 cells are implicated in the clinical phenotype characteristic of these patients. [ABSTRACT FROM AUTHOR]

The generation of protective antibodies by B cells following natural infection or vaccination requires 'help' from CD4+ T cells. T follicular helper (Tfh) cells are the specialized CD4+ T cell subset that has evolved the appropriate mechanisms to induce the activation and differentiation of B cells into immunoglobulin (Ig) secreting cells. As such, appropriate control of Tfh cell generation and function is essential to human health as overactivation is likely to result in autoimmunity, whereas underactivation is often associated with immunodeficiency. Furthermore, an understanding of the regulation of these cells may be invaluable to improved vaccine development strategies. Traditionally Tfh cells have been identified by their anatomical location in secondary lymphoid tissues, which has hindered the study of these cells in humans as access to these tissues is often not feasible. However, recent studies have identified the circulating counterparts to tissue Tfh cells and with this has come a wealth of knowledge gained from the study of these cells in human disease. Here we review some of the recent developments on the role of human Tfh cells in health and disease. [ABSTRACT FROM AUTHOR]

T follicular helper (TFH) cells are a specialized subset of CD4+ T cells that localize to B-cell follicles, where they are positioned to provide help for the induction of optimal humoral immune responses. Key features of TFH cells are the expressions of CXCR5, ICOS, interleukin (IL)-21 and BCL-6. The requirements for human TFH cell development are unknown. Here we show that IL-6, IL-12, IL-21 and IL-23 are capable of inducing IL-21 expression in naïve CD4+ T cells isolated from human tonsils, peripheral blood and cord blood. However, only IL-12 induced sustained expressions of CXCR5 and ICOS on these activated naïve CD4+ T cells, and endowed them with the ability to provide increased help to B cells for their differentiation into immunoglobulin-secreting cells. The effects of IL-12 were independent of interferon-γ and T-bet, and associated with upregulation of BCL-6 expression. Thus, these cytokines, particularly IL-12, are likely to act at an early stage during dendritic cell-mediated priming of naïve CD4+ T cells into a TFH cell fate, and thus underpin antibody-mediated immunity. [ABSTRACT FROM AUTHOR]

Lymphocyte differentiation is a complex process regulated bythe integration of signals received through a variety of cell surfacereceptors that results in populations of differentiated cells thathave acquired novel characteristics and effector functions. Differentiationof T and B lymphocytes into effector cells, such as cytokine-secretingCD4+ T cells, cytotoxic CD8+ Tcells and Ig-secreting B cells, as well as alterations in cell surface phenotype,have been reported to be associated with cell division. Nevertheless,the genesis of heterogeneity in effector cell type is unknown. Astrictly deterministic view holds that heterogeneity arises fromdistinct signalling histories for each functionally or phenotypicallydifferent cell type. In contrast, a probabilistic interpretation proposesthat internal stochastic regulation of gene expression gives riseto lymphocytes of mixed phenotypes. To help distinguish betweenthese explanations, we examined the expression of CD27, CCR7, CD45RAand CD45RO by human naive CD4+ T cells in thecontext of the division history of the lymphocyte. Our results showthat each marker independently changes with progressive divisions,strongly supporting the proposal that phenotypic heterogeneity inlymphocytes can arise as the result of independent stochastic processescontrolling the expression of individual molecules. [ABSTRACT FROM AUTHOR]