T cell antigen receptor-induced IL-2 production and apoptosis have different requirements for Lck activities.
The T cell hybridoma BI-141 has been previously used to dissect the roles of Lck in Ag-induced IL-2 production. Here we demonstrate that BI-141 undergoes apoptosis in response to TCR stimulation using Ag or anti-TCR Abs. Using a panel of BI-141 transfectants expressing constitutively activated Lck (F505) or phosphotyrosine-binding (K154F505 and C156F505) or kinase-impaired (R273F505) mutants, we assess the relative requirements for Lck in TCR-mediated IL-2 production and apoptosis. While BI-141 transfectants expressing F505 are dramatically enhanced in their ability to produce IL-2 in response to Ag relative to K154F505-, C156F505-, or R273F505-expressing transfectants, no differences between these transfectants are observed in their ability to undergo TCR-induced apoptosis. TCR-induced Fas ligand (FasL) expression is demonstrated to be dependent on Lck SH2 and kinase activities, although FasL expression cannot be correlated with apoptosis. Low levels of Fas are constitutively expressed at equal levels on transfectants and are not increased in response to TCR ligation. Together, these data indicate that TCR-induced apoptosis in BI-141 is regulated through a mechanism(s) distinct from the Lck-induced expression of Fas, FasL, or IL-2 production. This TCR signal may be independent of Lck kinase and SH2 activities, or may require lower threshold activity. The identification of differential requirements for particular T cell functions is crucial to understanding how TCR engagement affects downstream T cell functions and may aid in the rational design of therapeutics aimed at specifically modulating particular T cell responses.
Chung
C D
CD
Department of Microbiology and Immunology, University of California-Los Angeles School of Medicine, 90095, USA.
Lewis
L A
LA
Miceli
M C
MC
D000818:Animals; D017209:Apoptosis; D053222:Fas Ligand Protein; D007376:Interleukin-2 / Q000096:biosynthesis*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D019014:fas Receptor / Q000032:analysis; D018909:src Homology Domains
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)