Hegerl_and_Solomon_2009_Science[1] - PERSPECTIVES cells to...

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www.sciencemag.org SCIENCE VOL 325 21 AUGUST 2009 955 PERSPECTIVES a critical determinant of T FH cell generation. It will be interesting to see how different envi- ronmental cues affect the balance between these two transcriptional antagonists. Uncontrolled generation of T FH cells could be fatal, causing systemic autoimmunity by increasing antibody production. Therefore, expression of Blimp-1 may help maintain tol- erance by inhibiting Bcl6 expression and the differentiation of T FH cells. But if Bcl6 sup- presses the generation of T H 1 and T H 17 cells by binding to their master transcription fac- tors, then how are B cells stimulated to pro- duce antibodies in response to inteferon- γ and IL-17, the cytokines that these T cell subtypes secrete? One possibility is that B cells are induced to make these antibodies by T H 1 and T H 17 cells, instead of T FH cells, outside of ger- minal centers ( 13 ). Alternatively, differentiat- ing T H 1, T H 2, and T H 17 cells may express low amounts of Bcl6, which might allow them to acquire the T FH cell phenotype and induce B cells to make these antibodies. Johnston et al . show that a T cell–B cell interaction is essen- tial for Bcl6 expression in activated CD4 + T cells, which in turn could initiate differentia- tion into T FH cells. It might be possible that activated T H 1, T H 2, and T H 17 cells express Bcl6 upon interaction with B cells, causing them to become T FH 1, T FH 2, and T FH 17 cells. They could then affect antibody production by B cells through the cytokines they produce. The transcription factor cMaf also plays an essential role in generating T FH cells ( 14 ). cMaf primarily activates IL-21 expression in CD4 + T cells, and thus provides an auto- crine growth factor for T FH cell development ( 15 ). Bcl6 and cMaf may synergize to gen- erate T FH cells by regulating the expression of critical factors such as IL-21, the IL-21 receptor, and CXCR5. The balance among the transcription factors in the differentia- tion of T FH cells, particularly between Bcl6 and Blimp-1, could be exploited in various autoimmune and infectious diseases. References and Notes 1. L. J. McHeyzer-Williams, M. G. McHeyzer-Williams, Annu. Rev. Immunol. 23 , 487 (2005). 2. R. J. Johnston et al ., Science 325 , 1006 (2009); published online 16 July 2009 (10.1126/science. 1175870). 3. R. I. Nurieva et al, Science 325 , 1001 (2009); published online 23 July 2009 (10.1126/science. 1176676). 4. D. Yu et al ., Immunity 10.1016/j.immuni.2009.07.002 (2009). 5. N. Fazilleau et al ., Immunity 30 , 324 (2009). 6. A. G. Zaretsky et al ., J. Exp. Med. 206 , 991 (2009). 7. T. Korn et al ., Nature 448 , 484 (2007). 8. R. Nurieva et al ., Nature 448 , 480 (2007). 9. R. I. Nurieva
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Hegerl_and_Solomon_2009_Science[1] - PERSPECTIVES cells to...

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