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Casitas B-Lineage Lymphoma b Inhibits Antigen Recognition and Slows Cell Cycle Progression at Late Times during CD4⁺ T Cell Clonal Expansion¹

Department of Medicine and the Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455

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, PLC-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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the North Central Chapter Arthritis Foundation and National Institutes of Health Grants P01 AI35296 and R01 GM54706.

² Address correspondence and reprint requests to Dr. Daniel L. Mueller, Department of Medicine and Center for Immunology, University of Minnesota Medical School, MMC 334, 6-120 Nils Hasselmo Hall, 312 Church Street, Southeast, Minneapolis, MN 55455. E-mail address: muell002{at}umn.edu

³ Abbreviations used in this paper: Cbl-b, Casitas B-lineage lymphoma b; mTOR, mammalian target of rapamycin; PCCp, pigeon cytochrome c peptide 81-104; PKC, protein kinase C; Tg, transgenic; LN, lymph node.

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