T cells expressing receptors of different affinity for antigen ligands reveal a unique role for p59fyn in T cell development and optimal stimulation of T cells by antigen.
Signaling from the TCR involves the protein tyrosine kinase p59fyn (Fyn). Previous studies have shown that T cell development occurs normally in Fyn-/- mice. In this study, we investigated the requirement for Fyn in the development and function of T cells expressing either the transgenic 2C TCR, with high affinity for its Ag ligand, or the transgenic H-Y TCR, representative of a low affinity TCR. Although Fyn was not essential for positive selection of thymocytes expressing either the 2C or the H-Y TCR, it facilitated the down-regulation of the heat-stable Ag in positively selected CD4-CD8+ thymocytes in both 2C and H-Y mice. Negative selection of thymocytes expressing the H-Y TCR also occurs efficiently in Fyn-/- mice. However, in Fyn-/- mice, there was a preferential survival of thymocytes that expressed higher levels of the CD8 coreceptor and the transgenic TCR. Positively selected CD4-CD8+ thymocytes and peripheral T cells expressing either the 2C or the H-Y TCR differed in their requirement of Fyn for optimal proliferation responses to stimulation by antigenic ligands. Whereas 2C Fyn-/- or 2C Fyn+/+ thymocytes and peripheral T cells responded optimally to stimulation by the specific Ag, H-Y Fyn-/- thymocytes and peripheral T cells were hyporesponsive compared with Fyn+/+ cells. Significantly, in response to a defined low affinity ligand, both 2C Fyn-/- thymocytes and peripheral T cells required Fyn for optimal response to Ag stimulation. Thus, Fyn plays a role during thymocyte development and is required for optimal responses to low affinity/avidity ligands.
Utting
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Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
Teh
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Teh
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D000818:Animals; D000941:Antigens / Q000378:metabolism* / Q000494:pharmacology; D016827:CD8 Antigens / Q000032:analysis; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D006182:H-Y Antigen / Q000235:genetics / Q000378:metabolism; D016130:Immunophenotyping; D008024:Ligands; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D000941:Antigens; D016827:CD8 Antigens; D006182:H-Y Antigen; D008024:Ligands; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn