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Presents a study on T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6. Differentiation of CD4 T helper cells into T helper type 1 or 2; Materials and methods used in the study; Results.

Foxp3+ regulatory T (Treg) cells are essential to maintain immune homeostasis, yet controversy exists about the stability of this cell population. Bcl6-deficient (Bcl6−/−) mice develop severe and spontaneous T helper type 2 (Th2) inflammation and Bcl6-deficient Treg cells are ineffective at controlling Th2 responses. We used a lineage tracing approach to analyse the fate of Treg cells in these mice. In the periphery of Bcl6−/− mice, increased numbers of Foxp3-negative 'exTreg' cells were found, particularly in the CD25+ population. ExTreg cells from Bcl6−/− mice expressed increased interleukin-17 ( IL-17) and extremely elevated levels of Th2 cytokines compared with wild-type exTreg cells. Although Treg cells normally express only low levels of cytokines, Treg cells from Bcl6−/− mice secreted higher levels of IL-4, IL-5, IL-13 and IL-17 than wild-type conventional T cells. Next, Treg-specific conditional Bcl6-deficient (Bcl6Foxp3−/−) mice were analysed. Bcl6Foxp3−/− mice do not develop inflammatory disease, indicating a requirement for non-Treg cells for inflammation in Bcl6−/− mice, and have normal numbers of exTreg cells. We induced Th2-type allergic airway inflammation in Bcl6Foxp3−/− mice, and found that while exTreg cytokine expression was normal, Bcl6-deficient Treg cells expressed higher levels of the Th2-specific regulator Gata3 than Bcl6+ Treg cells. Bcl6Foxp3−/− mice had increased numbers of Th2 cells after induction of airway inflammation and increased T cells in the bronchoalveolar lavage fluid. These data show both Treg-intrinsic and Treg-extrinsic roles for Bcl6 in controlling Treg cell stability and Th2 inflammation, and support the idea that Bcl6 expression in Treg cells is critical for controlling Th2 responses. [ABSTRACT FROM AUTHOR]

Cytokine responsiveness is a critical component of the ability of cells to respond to the extracellular milieu. Transcription factor-mediated regulation of cytokine receptor expression is a common mode of altering responses to the external environment. We identify the transcription factor Twist1 as a component of a STAT3-induced feedback loop that controls IL-6 signals by directly repressing Il6ra. Human and mouse T cells lacking Twist1 have an increased ability to differentiate into Th17 cells. Mice with a T cell-specific deletion of Twist1 demonstrate increased Th17 and T follicular helper cell development, early onset experimental autoimmune encephalomyelitis, and increased antigen-specific antibody responses. Thus, Twist1 has a critical role in limiting both cell-mediated and humoral immunity. [ABSTRACT FROM AUTHOR]

Effective B cell-mediated immunity and antibody responses often require help from CD4 T cells. It is thought that a distinct CD4+ effector T cell subset, called T follicular helper cells (TFH), provides this help; however, the molecular requirements for TFH differentiation are unknown. We found that expression of the transcription factor Bcl6 in CD4+ cells is both necessary and sufficient for in vivo TFH differentiation and T cell help to B cells in mice. In contrast, the transcription factor Bilmp-1, an antagonist of Bcl6, inhibits TFH differentiation and help, thereby preventing B cell germinal center and antibody responses. These findings demonstrate that TFH cells are required for proper B cell responses in vivo and that Bcl6 and Blimp-1 play central but opposing roles in TFH differentiation. [ABSTRACT FROM AUTHOR]