Expression of human cathepsin L or human cathepsin V in mouse thymus mediates positive selection of T helper cells in cathepsin L knock-out mice
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Expression of human cathepsin L or human cathepsin V in mouse thymus mediates positive selection of T helper cells in cathepsin L knock-out mice. / Sevenich, Lisa; Hagemann, Sascha; Stoeckle, Christina; Tolosa, Eva; Peters, Christoph; Reinheckel, Thomas.
in: BIOCHIMIE, Jahrgang 92, Nr. 11, 01.11.2010, S. 1674-80.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Expression of human cathepsin L or human cathepsin V in mouse thymus mediates positive selection of T helper cells in cathepsin L knock-out mice
AU - Sevenich, Lisa
AU - Hagemann, Sascha
AU - Stoeckle, Christina
AU - Tolosa, Eva
AU - Peters, Christoph
AU - Reinheckel, Thomas
N1 - Copyright © 2010 Elsevier Masson SAS. All rights reserved.
PY - 2010/11/1
Y1 - 2010/11/1
N2 - A genetic deficiency of the cysteine protease cathepsin L (Ctsl) in mice results in impaired positive selection of conventional CD4+ T helper cells as a result of an incomplete processing of the MHC class II associated invariant chain or incomplete proteolytic generation of positively selecting peptide ligands. The human genome encodes, in contrast to the mouse genome, for two cathepsin L proteases, namely cathepsin L (CTSL) and cathepsin V (CTSV; alternatively cathepsin L2). In the human thymic cortex, CTSV is the predominately expressed protease as compared to CTSL or other cysteine cathepsins. In order to analyze the functions of CTSL and CTSV in the positive selection of CD4+ T cells we employed Ctsl knock-out mice crossed either with transgenic mice expressing CTSL under the control of its genuine human promoter or with transgenic mice expressing CTSV under the control of the keratin 14 (K14) promoter, which drives expression to the cortical epithelium. Both human proteases are expressed in the thymus of the transgenic mice, and independent expression of both CTSL and CTSV rescues the reduced frequency of CD4+ T cells in Ctsl-deficient mice. Moreover, the expression of the human cathepsins does not change the number of CD4+CD25+Foxp3+ regulatory T cells, but the normalization of the frequency of conventional CD4+ T cell in the transgenic mice results in a rebalancing of conventional T cells and regulatory T cells. We conclude that the functional differences of CTSL and CTSV in vivo are not mainly determined by their inherent biochemical properties, but rather by their tissue specific expression pattern.
AB - A genetic deficiency of the cysteine protease cathepsin L (Ctsl) in mice results in impaired positive selection of conventional CD4+ T helper cells as a result of an incomplete processing of the MHC class II associated invariant chain or incomplete proteolytic generation of positively selecting peptide ligands. The human genome encodes, in contrast to the mouse genome, for two cathepsin L proteases, namely cathepsin L (CTSL) and cathepsin V (CTSV; alternatively cathepsin L2). In the human thymic cortex, CTSV is the predominately expressed protease as compared to CTSL or other cysteine cathepsins. In order to analyze the functions of CTSL and CTSV in the positive selection of CD4+ T cells we employed Ctsl knock-out mice crossed either with transgenic mice expressing CTSL under the control of its genuine human promoter or with transgenic mice expressing CTSV under the control of the keratin 14 (K14) promoter, which drives expression to the cortical epithelium. Both human proteases are expressed in the thymus of the transgenic mice, and independent expression of both CTSL and CTSV rescues the reduced frequency of CD4+ T cells in Ctsl-deficient mice. Moreover, the expression of the human cathepsins does not change the number of CD4+CD25+Foxp3+ regulatory T cells, but the normalization of the frequency of conventional CD4+ T cell in the transgenic mice results in a rebalancing of conventional T cells and regulatory T cells. We conclude that the functional differences of CTSL and CTSV in vivo are not mainly determined by their inherent biochemical properties, but rather by their tissue specific expression pattern.
KW - Animals
KW - Antigens, CD4
KW - Cathepsin L
KW - Cathepsins
KW - Cysteine Endopeptidases
KW - Forkhead Transcription Factors
KW - Gene Expression
KW - Gene Knockout Techniques
KW - HLA-D Antigens
KW - Haplotypes
KW - Humans
KW - Interleukin-2 Receptor alpha Subunit
KW - Mice
KW - T-Lymphocytes, Helper-Inducer
KW - T-Lymphocytes, Regulatory
KW - Thymus Gland
KW - Transgenes
U2 - 10.1016/j.biochi.2010.03.014
DO - 10.1016/j.biochi.2010.03.014
M3 - SCORING: Journal article
C2 - 20347002
VL - 92
SP - 1674
EP - 1680
JO - BIOCHIMIE
JF - BIOCHIMIE
SN - 0300-9084
IS - 11
ER -