Cathepsin L: Critical Role in Ii Degradation and CD4 T Cell Selection in the Thymus

Science ◽  
1998 ◽  
Vol 280 (5362) ◽  
pp. 450-453 ◽  
Author(s):  
T. Nakagawa
Keyword(s):  
T Cell ◽  
Cathepsin L ◽  
Critical Role ◽  
Cd4 T Cell ◽  
Cell Selection ◽  
T Cell Selection

scholarly journals Cathepsin L Regulates CD4+ T Cell Selection Independently of Its Effect on Invariant Chain

2002 ◽  
Vol 195 (10) ◽  
pp. 1349-1358 ◽  
Author(s):  
Karen Honey ◽  
Terry Nakagawa ◽  
Christoph Peters ◽  
Alexander Rudensky
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Positive Selection ◽  
Cathepsin L ◽  
Cd4 T Cell ◽  
Thymic Epithelial Cells ◽  
Invariant Chain ◽  
Cell Selection ◽  
T Cell Selection

CD4+ T cells are positively selected in the thymus on peptides presented in the context of major histocompatibility complex class II molecules expressed on cortical thymic epithelial cells. Molecules regulating this peptide presentation play a role in determining the outcome of positive selection. Cathepsin L mediates invariant chain processing in cortical thymic epithelial cells, and animals of the I-Ab haplotype deficient in this enzyme exhibit impaired CD4+ T cell selection. To determine whether the selection defect is due solely to the block in invariant chain cleavage we analyzed cathepsin L–deficient mice expressing the I-Aq haplotype which has little dependence upon invariant chain processing for peptide presentation. Our data indicate the cathepsin L defect in CD4+ T cell selection is haplotype independent, and thus imply it is independent of invariant chain degradation. This was confirmed by analysis of I-Ab mice deficient in both cathepsin L and invariant chain. We show that the defect in positive selection in the cathepsin L−/− thymus is specific for CD4+ T cells that can be selected in a wild-type and provide evidence that the repertoire of T cells selected differs from that in wild-type mice, suggesting cortical thymic epithelial cells in cathepsin L knockout mice express an altered peptide repertoire. Thus, we propose a novel role for cathepsin L in regulating positive selection by generating the major histocompatibility complex class II bound peptide ligands presented by cortical thymic epithelial cells.

scholarly journals Ubiquitin ligase MARCH 8 cooperates with CD83 to control surface MHC II expression in thymic epithelium and CD4 T cell selection

2016 ◽  
Vol 213 (9) ◽  
pp. 1695-1703 ◽  
Author(s):  
Haiyin Liu ◽  
Reema Jain ◽  
Jing Guan ◽  
Vivian Vuong ◽  
Satoshi Ishido ◽  
...  
Keyword(s):  
T Cell ◽  
Ubiquitin Ligase ◽  
Cell Types ◽  
Surface Expression ◽  
Cd4 T Cell ◽  
Control Surface ◽  
Thymic Epithelial Cells ◽  
Cell Selection ◽  
Mhc Ii ◽  
T Cell Selection

Major histocompatibility complex class II (MHC II) expression is tightly regulated, being subjected to cell type–specific mechanisms that closely control its levels at the cell surface. Ubiquitination by the E3 ubiquitin ligase MARCH 1 regulates MHC II expression in dendritic cells and B cells. In this study, we demonstrate that the related ligase MARCH 8 is responsible for regulating surface MHC II in thymic epithelial cells (TECs). March8−/− mice have elevated MHC II at the surface of cortical TECs and autoimmune regulator (AIRE)− medullary TECs (mTECs), but not AIRE+ mTECs. Despite this, thymic and splenic CD4+ T cell numbers and repertoires remained unaltered in March8−/− mice. Notably, the ubiquitination of MHC II by MARCH 8 is controlled by CD83. Mice expressing a mutated form of CD83 (Cd83anu/anu mice) have impaired CD4+ T cell selection, but deleting March8 in Cd83anu/anu mice restored CD4+ T cell selection to normal levels. Therefore, orchestrated regulation of MHC II surface expression in TECs by MARCH 8 and CD83 plays a major role in CD4+ T cell selection. Our results also highlight the specialized use of ubiquitinating machinery in distinct antigen-presenting cell types, with important functional consequences and implications for therapeutic manipulation.

scholarly journals Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83

2016 ◽  
Vol 213 (9) ◽  
pp. 1685-1694 ◽  
Author(s):  
Julia von Rohrscheidt ◽  
Elisabetta Petrozziello ◽  
Jelena Nedjic ◽  
Christine Federle ◽  
Lena Krzyzak ◽  
...  
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Transmembrane Domain ◽  
Dendritic Cell Maturation ◽  
Functional Adaptation ◽  
Cd4 T Cell ◽  
Thymic Epithelial Cells ◽  
Cell Selection ◽  
Necessary And Sufficient ◽  
T Cell Selection

Deficiency of CD83 in thymic epithelial cells (TECs) dramatically impairs thymic CD4 T cell selection. CD83 can exert cell-intrinsic and –extrinsic functions through discrete protein domains, but it remains unclear how CD83’s capacity to operate through these alternative functional modules relates to its crucial role in TECs. In this study, using viral reconstitution of gene function in TECs, we found that CD83’s transmembrane domain is necessary and sufficient for thymic CD4 T cell selection. Moreover, a ubiquitination-resistant MHCII variant restored CD4 T cell selection in Cd83−/− mice. Although during dendritic cell maturation CD83 is known to stabilize MHCII through opposing the ubiquitin ligase March1, regulation of March1 did not account for CD83’s TEC-intrinsic role. Instead, we provide evidence that MHCII in cortical TECs (cTECs) is targeted by March8, an E3 ligase of as yet unknown physiological substrate specificity. Ablating March8 in Cd83−/− mice restored CD4 T cell development. Our results identify CD83-mediated MHCII stabilization through antagonism of March8 as a novel functional adaptation of cTECs for T cell selection. Furthermore, these findings suggest an intriguing division of labor between March1 and March8 in controlling inducible versus constitutive MHCII expression in hematopoietic antigen-presenting cells versus TECs.

scholarly journals Critical role for the common cytokine receptor gamma chain in intrathymic and peripheral T cell selection.

1996 ◽  
Vol 183 (3) ◽  
pp. 1111-1118 ◽  
Author(s):  
J P DiSanto ◽  
D Guy-Grand ◽  
A Fisher ◽  
A Tarakhovsky
Keyword(s):  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
T Cell Development ◽  
Cell Selection ◽  
Gamma Chain ◽  
Peripheral T Cells ◽  
The Common ◽  
T Cell Selection

The common cytokine receptor gamma chain (gammac), which is a functional subunit of the receptors for interleukins (IL)-2, -4, -7, -9, and -15, plays an important role in lymphoid development. Inactivation of this molecule in mice leads to abnormal T cell lymphopoiesis characterized by thymic hypoplasia and reduced numbers of peripheral T cells. To determine whether T cell development in the absence of gammac is associated with alterations of intrathymic and peripheral T cell selection, we have analyzed gammac-deficient mice made transgenic for the male-specific T cell receptor (TCR) HY (HY/gammac- mice). In HY/gammac- male mice, negative selection of autoreactive thymocytes was not diminished; however, peripheral T cells expressing transgenic TCR-alpha and -beta chains (TCR-alphaT/betaT) were absent, and extrathymic T cell development was completely abrogated. In HY/gammac- female mice, the expression of the transgenic TCR partially reversed the profound thymic hypoplasia observed in nontransgenic gammac- mice, generating increased numbers of thymocytes in all subsets, particularly the TCR-alphaT/betaT CD8+ single-positive thymocytes. Despite efficient positive selection, however, naive CD8+ TCR-alphaT/betaT T cells were severely reduced in the peripheral lymphoid organs of HY/gammac- female mice. These results not only underscore the indispensible role of gammac in thymocyte development, but also demonstrate the critical role of gammac in the maintenance and/or expansion of peripheral T cell pools.

Sign in / Sign up

Export Citation Format

Share Document