Casitas B-lineage lymphoma b inhibits antigen recognition and slows cell cycle progression at late times during CD4+ T cell clonal expansion.
Optimal clonal expansion of CD4(+) T cells during the primary response to Ag requires prolonged TCR recognition of peptide Ag/MHC complexes. In this study, we investigated the capacity of Casitas B-lineage lymphoma b (Cbl-b) to counter-regulate late TCR signals necessary for continued cell division in vivo. During the first 24 h of a primary response to Ag, Cblb(-/-) 5C.C7 CD4(+) T cells demonstrated no alteration in CD69, CD25, and CD71 up-regulation or cell growth as compared with wild-type cells. Nevertheless, beyond 24 h, both the expression of CD71 and the rate of cell division were increased in the genetic absence of Cbl-b, leading to an augmented clonal expansion. This deregulation of late T cell proliferation in the absence of Cbl-b resulted in part from an inability of Cblb(-/-) T cells to desensitize Akt, PLCgamma-1, and ERK phosphorylation events downstream of the TCR/CD3 complex, in addition to their failure to undergo a growth arrest in the absence of Ag. These observations now suggest a novel role for Cbl-b in triggering the exit from cell cycle at the end of a CD4(+) T cell clonal expansion.
Zhang
Ruan
R
Department of Medicine and the Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Zhang
Na
N
Mueller
Daniel L
DL
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000941:Antigens / Q000235:genetics / Q000276:immunology*; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D051966:Phospholipase C gamma / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D000941:Antigens; D015703:Antigens, CD; C118387:Cblb protein, mouse; D011948:Receptors, Antigen, T-Cell; D050721:Proto-Oncogene Proteins c-cbl; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051966:Phospholipase C gamma