A critical role for the autophagy gene Atg5 in T cell survival and proliferation

被引:515
作者
Pua, Heather H.
Dzhagalov, Ivan
Chuck, Mariana
Mizushima, Noboru
He, You-Wen [1 ]
机构
[1] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA
[2] Tokyo Metropolitan Inst Med Sci, Dept Bioregulat & Metab, Tokyo 1138613, Japan
[3] Japan Sci & Technol Agcy, SORST, Kawaguchi 3320012, Japan
关键词
D O I
10.1084/jem.20061303
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Macroautophagy (hereafter referred to as autophagy) is a well-conserved intracellular degradation process. Recent studies examining cells lacking the autophagy genes Atg5 and Atg7 have demonstrated that autophagy plays essential roles in cell survival during starvation, in innate cell clearance of microbial pathogens, and in neural cell maintenance. However, the role of autophagy in T lymphocyte development and survival is not known. Here, we demonstrate that autophagosomes form in primary mouse T lymphocytes. By generating Atg5(-/-) chimeric mice, we found that Atg5-deficient T lymphocytes underwent full maturation. However, the numbers of total thymocytes and peripheral T and B lymphocytes were reduced in Atg5 chimeras. In the periphery, Atg5(-/-) CD8(+) T lymphocytes displayed dramatically increased cell death. Furthermore, Atg5(-/-) CD4(+) and CD8(+) T cells failed to undergo efficient proliferation after TCR stimulation. These results demonstrate a critical role for Atg5 in multiple aspects of lymphocyte development and function and suggest that autophagy may be essential for both T lymphocyte survival and proliferation.
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页码:25 / 31
页数:7
相关论文
共 27 条
[1]   Autophagy: Dual roles in life and death? [J].
Baehrecke, EH .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2005, 6 (06) :505-510
[2]   Inhibition of macroautophagy triggers apoptosis [J].
Boya, P ;
González-Polo, RA ;
Casares, N ;
Perfettini, JL ;
Dessen, P ;
Larochette, N ;
Métivier, D ;
Meley, D ;
Souquere, S ;
Yoshimori, T ;
Pierron, G ;
Codogno, P ;
Kroemer, G .
MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (03) :1025-1040
[3]   Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4 [J].
Espert, Lucile ;
Denizot, Melanie ;
Grimaldi, Marina ;
Robert-Hebmann, Veronique ;
Gay, Bernard ;
Varbanov, Mihayl ;
Codogno, Patrice ;
Biard-Piechaczyk, Martine .
JOURNAL OF CLINICAL INVESTIGATION, 2006, 116 (08) :2161-2172
[4]   Autolysosomes accumulate during in vitro CD8+ T-lymphocyte aging and may participate in induced death sensitization of senescent cells [J].
Gerland, LM ;
Genestier, L ;
Peyrol, S ;
Michallet, MC ;
Hayette, S ;
Urbanowicz, I ;
Ffrench, P ;
Magaud, JP ;
Ffrench, M .
EXPERIMENTAL GERONTOLOGY, 2004, 39 (05) :789-800
[5]   Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages [J].
Gutierrez, MG ;
Master, SS ;
Singh, SB ;
Taylor, GA ;
Colombo, MI ;
Deretic, V .
CELL, 2004, 119 (06) :753-766
[6]   Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice [J].
Hara, Taichi ;
Nakamura, Kenji ;
Matsui, Makoto ;
Yamamoto, Akitsugu ;
Nakahara, Yohko ;
Suzuki-Migishima, Rika ;
Yokoyama, Minesuke ;
Mishima, Kenji ;
Saito, Ichiro ;
Okano, Hideyuki ;
Mizushima, Noboru .
NATURE, 2006, 441 (7095) :885-889
[7]   LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing [J].
Kabeya, Y ;
Mizushima, N ;
Uero, T ;
Yamamoto, A ;
Kirisako, T ;
Noda, T ;
Kominami, E ;
Ohsumi, Y ;
Yoshimori, T .
EMBO JOURNAL, 2000, 19 (21) :5720-5728
[8]   Loss of autophagy in the central nervous system causes neurodegeneration in mice [J].
Komatsu, Masaaki ;
Waguri, Satoshi ;
Chiba, Tomoki ;
Murata, Shigeo ;
Iwata, Jun-ichi ;
Tanida, Isei ;
Ueno, Takashi ;
Koike, Masato ;
Uchiyama, Yasuo ;
Kominami, Eiki ;
Tanaka, Keiji .
NATURE, 2006, 441 (7095) :880-884
[9]   The role of autophagy during the early neonatal starvation period [J].
Kuma, A ;
Hatano, M ;
Matsui, M ;
Yamamoto, A ;
Nakaya, H ;
Yoshimori, T ;
Ohsumi, Y ;
Tokuhisa, T ;
Mizushima, N .
NATURE, 2004, 432 (7020) :1032-1036
[10]   Protection against fatal Sindbis virus encephalitis by Beclin, a novel Bcl-2-interacting protein [J].
Liang, XH ;
Kleeman, LK ;
Jiang, HH ;
Gordon, G ;
Goldman, JE ;
Berry, G ;
Herman, B ;
Levine, B .
JOURNAL OF VIROLOGY, 1998, 72 (11) :8586-8596