The RhoA- and CDC42-specific exchange factor Dbs promotes expansion of immature thymocytes and deletion of double-positive and single-positive thymocytes.
Specific members of the Rho family of GTPases exert unique influences on thymocyte proliferation, differentiation and deletion. Dbs is a guanine nucleotide exchange factor which is expressed throughout thymocyte development and is able to activate the Rho family GTPases CDC42, RhoA and RhoG. Transgenic mice expressing an activated form of Dbs had increased numbers of double-negative thymocytes. The Dbs transgene promoted expansion of double-negative thymocytes in the absence of pre-TCR, but had no effect on pre-TCR-dependent differentiation of double-negative thymocytes into double-positive thymocytes. Transgenic double-positive thymocytes were proliferative in vivo, but were also susceptible to apoptosis in vivo and in vitro. The transgenic single-positive thymocytes had attenuated proliferative responses following TCR ligation, and were depleted rather than expanded during culture in the presence of anti-CD3. When expressing a positively selectable TCR, transgenic double-positive thymocytes were increased in number and activated, but the output of single-positive thymocytes was reduced. Transgenic double-positive thymocytes were acutely sensitive to deletion by TCR ligation in vivo. These results indicate that activation of Dbs has the potential to promote proliferation throughout thymocyte development, but also sensitizes double-positive and single-positive thymocytes to deletion.
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada.|present address: Department of Microbiology and Immunology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94122, USA.
Mark B
MB
Klinger
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
Benoit
B
Guilbault
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
Robert J
RJ
Kay
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D017637:Clonal Deletion; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000032:analysis / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D013234:Stem Cells / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; C092132:Mcf2l protein, mouse; D011948:Receptors, Antigen, T-Cell; D064067:Rho Guanine Nucleotide Exchange Factors; D020764:cdc42 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein