p59fyn (Fyn) promotes the survival of anergic CD4-CD8- alpha beta TCR+ cells but negatively regulates their proliferative response to antigen stimulation.
T cell anergy is characterized by alterations in TCR signaling that may play a role in controlling the unresponsiveness of the anergic cell. We have addressed questions regarding the importance of the Src kinase p59(fyn) (Fyn) in this process by using Fyn null mice. We demonstrate that a mature population of CD4(-)CD8(-) alphabeta TCR(+) anergic T cells lacking Fyn have a substantial recovery of their proliferation defect in response to Ag stimulation. This recovery cannot be explained by ameliorated production of IL-2, and the improved proliferation correlates with an enhanced ability of the Fyn(-/-) anergic T cells to up-regulate the high affinity IL-2 receptor. We also observe that anergic CD4(-)CD8(-) alphabeta TCR(+) T cells have a heightened survival ability that is partially dependent on the elevated levels of Fyn and IL-2 receptor beta-chain expressed by these cells. The enhanced survival correlates with an increased capacity of the anergic cells to respond to IL-15. We conclude that Fyn plays an important role in aspects of T cell anergy pertaining to TCR signaling and to cell survival.
Utting
O
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Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
Priatel
J J
JJ
Teh
S J
SJ
Teh
H S
HS
D000818:Animals; D000941:Antigens / Q000276:immunology*; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006183:H-2 Antigens / Q000235:genetics; D064532:Histocompatibility Antigen H-2D; D019409:Interleukin-15 / Q000378:metabolism / Q000502:physiology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis* / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D000941:Antigens; D015704:CD4 Antigens; D016827:CD8 Antigens; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D019409:Interleukin-15; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases