Abstract
Chaperone-mediated autophagy (CMA) targets soluble proteins for lysosomal degradation. Here we found that CMA was activated in T cells in response to engagement of the T cell antigen receptor (TCR), which induced expression of the CMA-related lysosomal receptor LAMP-2A. In activated T cells, CMA targeted the ubiquitin ligase Itch and the calcineurin inhibitor RCAN1 for degradation to maintain activation-induced responses. Consequently, deletion of the gene encoding LAMP-2A in T cells caused deficient in vivo responses to immunization or infection with Listeria monocytogenes. Impaired CMA activity also occurred in T cells with age, which negatively affected their function. Restoration of LAMP-2A in T cells from old mice resulted in enhancement of activation-induced responses. Our findings define a role for CMA in regulating T cell activation through the targeted degradation of negative regulators of T cell activation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / immunology
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Animals
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Autophagy / immunology*
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / biosynthesis
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
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Calcineurin Inhibitors / metabolism
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Calcium-Binding Proteins
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Cells, Cultured
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Dual Oxidases
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Female
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Humans
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Immunization
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Intracellular Signaling Peptides and Proteins / metabolism
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Listeria monocytogenes / immunology
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Listeriosis / immunology
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Lymphocyte Activation / immunology*
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Lysosomal-Associated Membrane Protein 2 / biosynthesis
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Lysosomal-Associated Membrane Protein 2 / genetics
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Lysosomal-Associated Membrane Protein 2 / immunology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Molecular Chaperones / immunology*
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Muscle Proteins / metabolism
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NADPH Oxidases / genetics
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Oxidative Stress / immunology
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RNA Interference
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RNA, Messenger / biosynthesis
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RNA, Small Interfering
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Reactive Oxygen Species / metabolism
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Receptors, Antigen, T-Cell / immunology
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Th1 Cells / immunology*
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Ubiquitin-Protein Ligases / metabolism
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Calcineurin Inhibitors
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Calcium-Binding Proteins
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DSCR1 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Lysosomal-Associated Membrane Protein 2
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Molecular Chaperones
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Muscle Proteins
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RNA, Messenger
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RNA, Small Interfering
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Reactive Oxygen Species
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Receptors, Antigen, T-Cell
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Tcfeb protein, mouse
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Dual Oxidases
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NADPH Oxidases
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Duox1 protein, mouse
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Itch protein, mouse
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Ubiquitin-Protein Ligases