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MEKK3 Is Essential for Lymphopenia-Induced T Cell Proliferation and Survival¹

Xiaofang Wang^*, Xing Chang^*, Valeria Facchinetti, Yuan Zhuang and Bing Su^2,*,

^* Department of Immunobiology and Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06520; Department of Immunology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030; and Department of Immunology, Duke University Medical Center, Durham, NC 27710

T cell homeostasis is crucial for maintaining an efficient and balanced T cell immunity. The interaction between TCR and self peptide (sp) MHC ligands is known to be the key driving force in this process, and it is believed to be functionally and mechanistically different from that initiated by the antigenic TCR stimulation. Yet, very little is known about the downstream signaling events triggered by this TCR-spMHC interaction and how they differ from those triggered by antigenic TCR stimulation. In this study, we show that T cell conditional ablation of MEKK3, a Ser/Thr kinase in the MAPK cascade, causes a significant reduction in peripheral T cell numbers in the conditional knockout mice, but does not perturb thymic T cell development and maturation. Using an adoptive mixed transfer method, we show that MEKK3-deficient T cells are severely impaired in lymphopenia-induced cell proliferation and survival. Interestingly, the Ag-induced T cell proliferation proceeds normally in the absence of MEKK3. Finally, we found that the activity of ERK1/2, but not p38 MAPK, was attenuated during the lymphopenia-driven response in MEKK3-deficient T cells. Together, these data suggest that MEKK3 may play a crucial selective role for spMHC-mediated T cell homeostasis.

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 in part by National Institutes of Health Grant AI 063348 (to B.S.), GM 59638 (to Y.Z.), and American Heart Association Grant 0765060Y (to V.F.). X.C. is a recipient of Gershon/Trudeau Fellowship from Immunobiology at Yale University.

² Address correspondence and reprint requests to Dr. Bing Su. 10 Amistad Street, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520. E-mail address: bing.su{at}yale.edu

³ Abbreviations used in this paper: LIP, lymphopenia-induced proliferation; 7-AAD, 7-aminoactinomycin D; BMDCs, bone marrow-derived dentritic cells; DN, double negative; DP, double positive; ES, embryonic stem; f.p., fast proliferating; KO, knockout; LN, lymph node; MAP3K, MAPK kinase kinase; NCL, normal control littermate; sp, self peptide; SP, single positive; WT, wild type.

⁴ The online version of this article contains supplemental material.