The Ubiquitin-like Modifier FAT10 Is Selectively Expressed in Medullary Thymic Epithelial Cells and Modifies 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.

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

Journal of Experimental Medicine ◽

10.1084/jem.20160316 ◽

2016 ◽

Vol 213 (9) ◽

pp. 1685-1694 ◽

Cited By ~ 36

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.20160312 ◽

2016 ◽

Vol 213 (9) ◽

pp. 1695-1703 ◽

Cited By ~ 26

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.

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Faculty Opinions recommendation of Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3539966.3239064 ◽

2010 ◽

Author(s):

Michael Farrar ◽

Kieng Bao Vang

Keyword(s):

T Cell ◽

Epithelial Cells ◽

Cd4 T Cell ◽

Thymic Epithelial Cells ◽

T Cell Tolerance ◽

Cell Tolerance ◽

Medullary Thymic Epithelial Cells

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RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla

Journal of Experimental Medicine ◽

10.1084/jem.20062497 ◽

2007 ◽

Vol 204 (6) ◽

pp. 1267-1272 ◽

Cited By ~ 334

Author(s):

Simona W. Rossi ◽

Mi-Yeon Kim ◽

Andreas Leibbrandt ◽

Sonia M. Parnell ◽

William E. Jenkinson ◽

...

Keyword(s):

T Cell ◽

Epithelial Cells ◽

Molecular Mechanisms ◽

Cell Receptor ◽

Thymic Epithelial Cells ◽

Receptor Repertoire ◽

Thymic Medulla ◽

Medullary Thymic Epithelial Cells ◽

Functional Regulation ◽

Lymphoid Structures

Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4+3− inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus. CD4+3− cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire+ mTECs. We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80−Aire− mTEC progenitors into CD80+Aire+ mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire+ mTECs and highlight a previously unrecognized role for CD4+3−RANKL+ inducer cells in intrathymic self-tolerance.

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