The Journal of Immunology, Vol 152, Issue 6 2853-2859, Copyright © 1994 by American Association of Immunologists

ARTICLES

Cyclosporin A inhibits positive selection and delays negative selection in alpha beta TCR transgenic mice

KB Urdahl, DM Pardoll and MK Jenkins
Department of Microbiology, University of Minnesota, Minneapolis 55455.

Cyclosporin A (CsA) is an immunosuppressive drug that inhibits TCR- mediated signal transduction. This drug has two major effects on developing alpha beta thymocytes in normal mice: it blocks the development of most mature CD4+8- and CD4-8+ thymocytes and inhibits the deletion of some but not all self-specific thymocytes. The latter effect may explain how CsA treatment can paradoxically induce autoimmunity in certain situations. Here we investigated the effects of CsA on thymocyte development in transgenic mice that express on most of their T cells an alpha beta TCR specific for male H-Y Ag bound to H-2 Db class I molecules, a model system in which positive and negative selection have been clearly defined. Positive selection occurs in female mice, resulting in the development of mature CD4-CD8+ T cells, whereas negative selection occurs in male mice, resulting in the deletion of self-reactive CD4+8+ thymocytes. CsA blocked positive selection, as evidenced by the finding that most of the cells present in the thymuses of CsA-treated female mice were functionally immature precursors that expressed heat-stable Ag. In male mice, CsA delayed but did not prevent the deletion of most CD4+8+ thymocytes. A few transgenic thymocytes, however, were not deleted and achieved the TCR+, CD4-8+ phenotype of positively selected cells. Therefore, for a small subset of thymocytes, CsA may convert a normally negatively selecting TCR signal to a positively selecting one.

This article has been cited by other articles:

				K. Ramsey, N. Luckashenak, G. A. Koretzky, and J. L. Clements Impaired thymic selection in mice expressing altered levels of the SLP-76 adaptor protein J. Leukoc. Biol., February 1, 2008; 83(2): 419 - 429. [Abstract] [Full Text] [PDF]

				A. K. Patra, T. Drewes, S. Engelmann, S. Chuvpilo, H. Kishi, T. Hunig, E. Serfling, and U. H. Bommhardt PKB Rescues Calcineurin/NFAT-Induced Arrest of Rag Expression and Pre-T Cell Differentiation J. Immunol., October 1, 2006; 177(7): 4567 - 4576. [Abstract] [Full Text] [PDF]

				P. A. Sieling, W. Chung, B. T. Duong, P. J. Godowski, and R. L. Modlin Toll-Like Receptor 2 Ligands as Adjuvants for Human Th1 Responses J. Immunol., January 1, 2003; 170(1): 194 - 200. [Abstract] [Full Text] [PDF]

				O. F. Bueno, E. B. Brandt, M. E. Rothenberg, and J. D. Molkentin Defective T cell development and function in calcineurin Abeta -deficient mice PNAS, July 9, 2002; 99(14): 9398 - 9403. [Abstract] [Full Text] [PDF]

				Y. Amasaki, S. Adachi, Y. Ishida, M. Iwata, N. Arai, K.-i. Arai, and S. Miyatake A Constitutively Nuclear Form of NFATx Shows Efficient Transactivation Activity and Induces Differentiation of CD4+CD8+ T Cells J. Biol. Chem., July 5, 2002; 277(28): 25640 - 25648. [Abstract] [Full Text] [PDF]

				V. Raman, F. Blaeser, N. Ho, D. L. Engle, C. B. Williams, and T. A. Chatila Requirement for Ca2+/Calmodulin-Dependent Kinase Type IV/Gr in Setting the Thymocyte Selection Threshold J. Immunol., December 1, 2001; 167(11): 6270 - 6278. [Abstract] [Full Text] [PDF]

				K. Hayden-Martinez, L. P. Kane, and S. M. Hedrick Effects of a Constitutively Active Form of Calcineurin on T Cell Activation and Thymic Selection J. Immunol., October 1, 2000; 165(7): 3713 - 3721. [Abstract] [Full Text] [PDF]

				B. Nikolic, G. Zhao, K. Swenson, and M. Sykes A novel application of cyclosporine A in nonmyeloablative pretransplant host conditioning for allogeneic BMT Blood, August 1, 2000; 96(3): 1166 - 1172. [Abstract] [Full Text] [PDF]

				P. F. Mixter, J. Q. Russell, G. J. Morrissette, C. Charland, D. Aleman-Hoey, and R. C. Budd A Model for the Origin of TCR-{alpha}{beta}+ CD4-CD8- B220+ Cells Based on High Affinity TCR Signals J. Immunol., May 15, 1999; 162(10): 5747 - 5756. [Abstract] [Full Text] [PDF]

				W. Chen, C. Thoburn, and A. D. Hess Characterization of the Pathogenic Autoreactive T Cells in Cyclosporine-Induced Syngeneic Graft-Versus-Host Disease J. Immunol., December 15, 1998; 161(12): 7040 - 7046. [Abstract] [Full Text] [PDF]

				G. M. Davey, S. L. Schober, B. T. Endrizzi, A. K. Dutcher, S. C. Jameson, and K. A. Hogquist Preselection Thymocytes Are More Sensitive to T Cell Receptor Stimulation Than Mature T Cells J. Exp. Med., November 16, 1998; 188(10): 1867 - 1874. [Abstract] [Full Text] [PDF]

				I. Ferrero, F. Anjuere, I. Azcoitia, T. Renno, H. R. MacDonald, and C. Ardavin Viral Superantigen-Induced Negative Selection of TCR Transgenic CD4+ CD8+ Thymocytes Depends on Activation, but not Proliferation Blood, June 1, 1998; 91(11): 4248 - 4254. [Abstract] [Full Text] [PDF]

				M Iwata, Y Ohoka, T Kuwata, and A Asada Regulation of T cell apoptosis via T cell receptors and steroid receptors Stem Cells, November 1, 1996; 14(6): 632 - 641. [Abstract]