Following activation, CD4+ T cells differentiate into different lineages of helper T (T(H)) cells that are characterized by distinct developmental regulation and biological functions. T(H)17 cells have recently been identified as a new lineage of effector T(H) cells, and they have been shown to be important in immune responses to infectious agents, as well as in various immune diseases. Over the past two to three years, there has been a rapid progress in our understanding of the differentiation programme of T(H)17 cells. Here, I summarize our current knowledge of the unique gene expression, cytokine-mediated regulation and transcriptional programming of T(H)17 cells, and provide my personal perspectives on the future studies that are required to elucidate this lineage in more detail.

TH17 cells in development: an updated view of their molecular identity and genetic programming.

Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly.

/pdf/il-21-regulates-germinal-center-b-cell-differentiation-and-cd4rhpis2g.pdf

IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism.

Interleukin-21 (IL-21), a potent immunomodulatory four-α-helical-bundle type I cytokine, is produced by NKT and CD4+ T cells and has pleiotropic effects on both innate and adaptive immune responses. These actions include positive effects such as enhanced proliferation of lymphoid cells, increased cytotoxicity of CD8+ T cells and natural killer (NK) cells, and differentiation of B cells into plasma cells. Conversely, IL-21 also has direct inhibitory effects on the antigen-presenting function of dendritic cells and can be proapoptotic for B cells and NK cells. IL-21 is also produced by Th17 cells and is a critical regulator of Th17 development. The regulatory activity of IL-21 is modulated by the differentiation state of its target cells as well as by other cytokines or costimulatory molecules. IL-21 has potent antitumor activity but is also associated with the development of autoimmune disease. IL-21 transcription is dependent on a calcium signal and NFAT sites, and IL-21 requires Stat3 for its signaling. ...

/pdf/interleukin-21-basic-biology-and-implications-for-cancer-and-3exnyl15gp.pdf

Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity*

Natural killer T cells (NKT cells) are CD1d-restricted, lipid antigen–reactive, immunoregulatory T lymphocytes that can promote cell-mediated immunity to tumors and infectious organisms, including bacteria and viruses, yet paradoxically they can also suppress the cell-mediated immunity associated with autoimmune disease and allograft rejection. Furthermore, in some diseases, such as atherosclerosis and allergy, NKT cell activity can be deleterious to the host. Although the precise means by which these cells carry out such contrasting functions is unclear, recent studies have highlighted the existence of many functionally distinct NKT cell subsets. Because their frequency and number vary widely between individuals, it is important to understand the mechanisms that regulate the development and maintenance of NKT cells and subsets thereof, which is the subject of this review.

Raising the NKT cell family

NKT cell subsets can be divided based on CD4 and NK1.1 expression and tissue of origin, but the developmental and functional relationships between the different subsets still are poorly understood. A comprehensive study of 19 cytokines across different NKT cell subsets revealed that no two NKT subpopulations exhibited the same cytokine profile, and, remarkably, the amounts of each cytokine produced varied by up to 100-fold or more among subsets. This study also revealed the existence of a population of CD4−NK1.1− NKT cells that produce high levels of the proinflammatory cytokine IL-17 within 2–3 h of activation. On intrathymic transfer these cells develop into mature CD4−NK1.1+ but not into CD4+NK1.1+ NKT cells, indicating that CD4−NK1.1− NKT cells include an IL-17–producing subpopulation, and also mark the elusive branch point for CD4+ and CD4− NKT cell sublineages.

https://www.pnas.org/content/pnas/105/32/11287.full.pdf

Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1- NKT cell population.

Epidemiological studies have suggested that the recent increase in the incidence and severity of immunoglobulin (Ig)E-mediated allergic disorders is inversely correlated with Mycobacterium bovis bacillus Calmette Guerin (BCG) vaccination; however, the underlying mechanisms remain uncertain. Here, we demonstrate that natural killer T (NKT) cells in mice and humans play a crucial role in the BCG-induced suppression of IgE responses. BCG-activated murine Valpha14 NKT cells, but not conventional CD4 T cells, selectively express high levels of interleukin (IL)-21, which preferentially induces apoptosis in Bepsilon cells. Signaling from the IL-21 receptor increases the formation of a complex between Bcl-2 and the proapoptotic molecule Bcl-2-modifying factor, resulting in Bepsilon cell apoptosis. Similarly, BCG vaccination induces IL-21 expression by human peripheral blood mononuclear cells (PBMCs) in a partially NKT cell-dependent fashion. BCG-activated PBMCs significantly reduce IgE production by human B cells. These findings provide new insight into the therapeutic effect of BCG in allergic diseases.

/pdf/il-21-induced-be-cell-apoptosis-mediated-by-natural-killer-t-1g95rpr02c.pdf

Wen Chen Yeh

Papers

IL-21-induced Bε cell apoptosis mediated by natural killer T cells suppresses IgE responses