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Unformatted text preview: Interleukin 17–producing CD4 + effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages Laurie E Harrington 1 , Robin D Hatton 1 , Paul R Mangan 1 , Henrietta Turner 1 , Theresa L Murphy 2 , Kenneth M Murphy 2 & Casey T Weaver 1 CD4 + T cells producing interleukin 17 (IL-17) are associated with autoimmunity, although the precise mechanisms that control their development are undefined. Here we present data that challenge the idea of a shared developmental pathway with T helper type 1 (T H 1) or T H 2 lineages and instead favor the idea of a distinct effector lineage we call ‘T H-17’. The development of T H-17 cells from naive precursor cells was potently inhibited by interferon- c (IFN- c ) and IL-4, whereas committed T H-17 cells were resistant to suppression by T H 1 or T H 2 cytokines. In the absence of IFN- c and IL-4, IL-23 induced naive precursor cells to differentiate into T H-17 cells independently of the transcription factors STAT1, T-bet, STAT4 and STAT6. These findings provide a basis for understanding how inhibition of IFN- c signaling enhances development of pathogenic T H-17 effector cells that can exacerbate autoimmunity. The antigen-driven differentiation of naive T cells into effector cells under the guidance of developmental cues from cells of the innate immune system is central to adaptive immunity. Classically, effector CD4 + T cells have been assigned to the T helper type 1 (T H 1) or T H 2 lineage based on their cytokine profiles 1,2 . T H 1 cells evolved to enhance clearance of intracellular pathogens and are defined on the basis of their production of interferon- g (IFN- g ). T H 2 cells are critical for the control of certain parasitic infections through the production of the clustered group of cytokines interleukin 4 (IL-4), IL-5 and IL-13. Both lineages have been associated with immune pathogenesis in the setting of dysregulated or unchecked activation. Thus, T H 1 cells have been linked to many chronic autoinflammatory disorders, whereas T H 2 cells are linked to atopy and asthma. Substantial advances have been made in understanding the devel- opmental pathways that give rise to T H 1 and T H 2 cells 3–6 . T H 1 cell development is coupled to the sequential involvement of cell-extrinsic and cell-intrinsic factors, including signal transducer and transcription activator 1 (STAT1), the transcription factor T-bet, IL-12 and STAT4, whereas T H 2 cell development is coupled to IL-4, STAT6 and the transcription factor GATA-3. Notably, cytokines produced by mature effector cells of each lineage can reinforce their own developmental program through positive and negative feedback acting on both naive T cells and innate immune cells. Thus, IFN- g produced by mature T H 1 cells or innate immune cells, and IL-27, an IL-12 family member produced by innate immune cells, induce STAT1 signaling and T-bet expression in antigen-activated, naive CD4 + T cells, leading to upregulation of the IL-12 receptor (IL-12R) on developing T...
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This note was uploaded on 01/03/2012 for the course BI 144 taught by Professor List during the Fall '10 term at Caltech.
- Fall '10