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CIITA Expression and Th1-Th2 Balance

Cheong-Hee Chang^*, Tania Gourley and Dipak Patel^*

^* Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46256 Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322

We have previously described a role for the MHC class II transactivator (CIITA) in the regulation of appropriate cytokine expression in Th subsets (1). CIITA-deficient Th1 cells from mice that ectopically expressed I-E expressed high levels of IL-4 and IFN-, suggesting that CIITA may play a role in eliminating IL-4 expression in the Th2 phenotype. In contrast, Otten et al. (2) recently reported an analysis of CIITA transgenic mice that showed a Th2 skewed phenotype. The authors suggested that one explanation for the Th1/Th2 imbalance is from MHC class II over-expression, and not from the lack of CIITA. However, we think this explanation is unlikely. In our report, we included a control group of A^-/- mice reconstituted with the I-E MHC class II transgene (1). Therefore, both the experimental and the control group mice expressed the same MHC class II transgene and the only difference between the two was CIITA expression. If MHC class II expression was the key, both groups would have shown a similar Th2 skewed phenotype. As we have reported, the control group did not exhibit an altered profile of cytokine production (1). This suggests that the absence of CIITA, not the expression of MHC class II, results in the observed phenotype. Taken together, proper expression of the CIITA gene (temporally and quantitatively) seems to be important in maintaining proper Th cytokine profiles. Both transgenic over-expression, as well as a complete absence of CIITA, at the wrong time would perturb the programming of Th cell differentiation.

	References

Top References References

 

1. Gourley, T., S. Roys, N. Lukacs, S. Kunkel, R. A. Flavell, C.-H. Chang. 1999. A novel role for the major histocompatibility complex class II transactivator CIITA in the repression of IL-4 production. Immunity 10:377.[Medline]
2. Otten, L. A., F. Tacchini-Cottier, M. Lohoff, F. Annunziato, L. Cosmi, L. Scarpellino, J. Louis, V. Steimle, W. Reith, H. Acha-Orbea. 2003. Deregulated MHC class II transactivator expression leads to a strong Th2 bias in CD4⁺ T lymphocytes. J. Immunol. 170:1150.[Abstract/Free Full Text]

The authors respond

Luc A. Otten, Walter Reith and Hans Acha-Orbea^,¶

Institute of Biochemistry, University of Lausanne, Epalinges Switzerland Department of Genetics and Microbiology, University of Geneva Medical School, Geneva, Switzerland ^¶ Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland

Gourley et al. (R1 ) described an increased IL-4 expression in Th1 cells derived from CIITA^-/- mice carrying an ectopically expressed I-E transgene. As this was not observed in Th1 cells from control I-A^-/- mice carrying the same I-E transgene, the increased IL-4 expression was attributed to the absence of CIITA in Th1 cells (R1 ), which was claimed to be the only difference between the two types of mutant mice. However, the two groups of mice differ by more than just CIITA expression. In addition to classical MHC class II genes, CIITA also controls expression of accessory molecules required for MHC class II restricted Ag presentation, namely H-2M, H-2O, and invariant chain (R2 ). Therefore the I-E transgenic CIITA^-/- mice are expected to have a general defect in MHC class II restricted Ag presentation, while this is not the case for the I-E transgenic I-A^-/- controls, in which the Ag presentation machinery remains intact on APC.

We believe that the increased IL-4 expression described by Gourley et al. could thus be an indirect consequence of deregulated MHC class II restricted Ag presentation rather than a direct result of the absence of CIITA in Th1 cells. We raised this possibility because enhanced IL-4 expression is also observed when the normal pattern of MHC class II restricted Ag presentation is perturbed in a wild-type background by a ubiquitously expressed CIITA transgene (R3 ). In addition, it is striking that CIITA expression is similar in Th1 and Th2 cells (R3 ). In our view, the expression of all genes involved in MHC class II restricted Ag presentation must be taken into account to resolve this interesting issue concerning the mechanism inducing the Th2 bias. In this respect it would be important to examine Th cell differentiation in mice expressing the I-E transgene on other mutant backgrounds, such as in mice lacking H-2M. The presence of a Th2 bias in such mice as well would support our interpretation that a correctly regulated pattern of MHC class II expression is essential for a proper Th1-Th2 balance.

	References

Top References References

 

1. Gourley, T., S. Roys, N. Lukacs, S. Kunkel, R. A. Flavell, C.-H. Chang. 1999. A novel role for the major histocompatibility complex class II transactivator CIITA in the repression of IL-4 production. Immunity 10:377.
2. Ting, J. P., J. Trowsdale. 2002. Genetic control of MHC class II expression. Cell 109:(Suppl.):S21.
3. Otten, L. A., F. Tacchini-Cottier, M. Lohoff, F. Annunziato, L. Cosmi, L. Scarpellino, J. Louis, V. Steimle, W. Reith, H. Acha-Orbea. 2003. Deregulated MHC class II transactivator expression leads to a strong Th2 bias in CD4⁺ T lymphocytes. J. Immunol. 170:1150.

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				W. S. Park, Y. Bae, D. H. Chung, Y.-L. Choi, B. K. Kim, Y. C. Sung, E. Y. Choi, S. H. Park, and K. C. Jung T cell expression of CIITA represses Th1 immunity Int. Immunol., October 1, 2004; 16(10): 1355 - 1364. [Abstract] [Full Text] [PDF]

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