GILT in Thymic Epithelial Cells Facilitates Central CD4 T Cell Tolerance to a Tissue-Restricted, Melanoma-Associated Self-Antigen

T cell tolerance depends upon Aire-expressing cells to purge the T cell repertoire of autoreactive clones. Once thought to be the exclusive domain of thymic epithelial cells, a new study by Yamano et al. (https://doi.org/10.1084/jem.20181430) in this issue of JEM identifies ILC3-like cells in the lymph nodes with similar properties.

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Strong T cell tolerance in parent----F1 bone marrow chimeras prepared with supralethal irradiation. Evidence for clonal deletion and anergy.

Journal of Experimental Medicine ◽

10.1084/jem.171.4.1101 ◽

1990 ◽

Vol 171 (4) ◽

pp. 1101-1121 ◽

Cited By ~ 81

Author(s):

E K Gao ◽

D Lo ◽

J Sprent

Keyword(s):

T Cells ◽

T Cell ◽

Epithelial Cells ◽

Tolerance Induction ◽

Thymic Epithelial Cells ◽

T Cell Tolerance ◽

Cell Tolerance ◽

Cd4 Cells ◽

Clonal Deletion ◽

Host Type

T cell tolerance induction was examined in long-term H-2-heterozygous parent----F1 chimeras prepared with supralethal irradiation (1,300 rad). Although these chimeras appeared to be devoid of host-type APC, the donor T cells developing in the chimeras showed marked tolerance to host-type H-2 determinants. Tolerance to the host appeared to be virtually complete in four assay systems: (a) primary mixed lymphocyte reactions (MLR) of purified lymph node (LN) CD8+ cells (+/- IL-2); (b) primary MLR of CD4+ (CD8-) thymocytes; (c) skin graft rejection; and (d) induction of lethal graft-vs.-host disease by CD4+ cells. Similar tolerance was observed in chimeras given double irradiation. The only assay in which the chimera T cells failed to show near-total tolerance to the host was the primary MLR of post-thymic CD4+ cells. In this assay, LN CD4+ cells regularly gave a significant antihost MLR. The magnitude of this response was two- to fourfold less than the response of normal parental strain CD4+ cells and, in I-E(-)----I-E+ chimeras, was paralleled by approximately 70% deletion of V beta 11+ cells. Since marked tolerance was evident at the level of mature thymocytes, tolerance induction in the chimeras presumably occurred in the thymus itself. The failure to detect host APC in the thymus implies that tolerance reflected contact with thymic epithelial cells (and/or other non-BM-derived cells in the thymus). To account for the residual host reactivity of LN CD4+ cells and the incomplete deletion of V beta 11+ cells, it is suggested that T cell contact with thymic epithelial cells induced clonal deletion of most of the host-reactive T cells but spared a proportion of these cells (possibly low affinity cells). Since these latter cells appeared to be functionally inert in the thymus (in contrast to LN), we suggest that the thymic epithelial cells induced a temporary form of anergy in the remaining host-reactive thymocytes. This anergic state disappeared when the T cells left the thymus and reached LN.

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Engineered Dendritic Cell-Directed Concurrent Activation of Multiple T cell Inhibitory Pathways Induces Robust Immune Tolerance

10.1101/706937 ◽

2019 ◽

Author(s):

Radhika R. Gudi ◽

Subha Karumuthil-Melethil ◽

Nicolas Perez ◽

Gongbo Li ◽

Chenthamarakshan Vasu

Keyword(s):

T Cell ◽

Antigen Presentation ◽

Immune Tolerance ◽

Cd4 T Cell ◽

T Cell Tolerance ◽

Cell Tolerance ◽

Inhibitory Receptors ◽

Activated T Cells ◽

Autoantibody Production ◽

Self Antigen

AbstractInhibitory/repressor-receptors are upregulated significantly on activated T cells, and have been the molecules of attention as targets for inducing immune tolerance. Induction of effective antigen specific tolerance depends on concurrent engagement of the TCR and one or more of these inhibitory receptors. Here, we show, for the first time that dendritic cells (DCs) can be efficiently engineered to express multiple T cell inhibitory ligands, and enhanced engagement of T cell inhibitory receptors, upon antigen presentation, by these DCs can induce effective CD4+ T cell tolerance and suppress autoimmunity. Compared to control DCs, antigen presentation by DCs that ectopically express CTLA4, PD1 and BTLA selective ligands (B7.1wa, PD-L1, and HVEM-CRD1 respectively) individually (mono-ligand DCs) or in combination (multi-ligand DCs) causes an inhibition of CD4+ T cell proliferation and pro-inflammatory cytokine response, as well as increase in Foxp3+ Treg frequency and immune regulatory cytokine production. Administration of self-antigen (mouse thyroglobulin; mTg) loaded multi-ligand DCs caused hyporesponsiveness to mTg challenge, suppression of autoantibody production, and amelioration of experimental autoimmune thyroiditis. Overall, this study shows that engineered DC-directed enhanced concurrent activation of multiple T cell coinhibitory pathways is an effective way to induce self-antigen specific T cell tolerance to suppress ongoing autoimmunity.

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Restricted expression of transgenic HLA-DRA gene in thymic epithelial cells and its role in acquisition of T cell tolerance to self-superantigens and processed DRα-derived peptide

European Journal of Immunology ◽

10.1002/eji.1830230742 ◽

1993 ◽

Vol 23 (7) ◽

pp. 1678-1686 ◽

Cited By ~ 6

Author(s):

Yoshinori Fukui ◽

Ken Yamamoto ◽

Nobuhiko Yokoyama ◽

Tomohisa Iwanaga ◽

Chieri Kurashima ◽

...

Keyword(s):

T Cell ◽

Epithelial Cells ◽

Thymic Epithelial Cells ◽

T Cell Tolerance ◽

Cell Tolerance

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Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation

Nature Reviews Immunology ◽

10.1038/s41577-018-0083-6 ◽

2018 ◽

Vol 19 (1) ◽

pp. 7-18 ◽

Cited By ~ 49

Author(s):

Ludger Klein ◽

Ellen A. Robey ◽

Chyi-Song Hsieh

Keyword(s):

Cell Differentiation ◽

T Cell ◽

Regulatory T Cell ◽

T Cell Differentiation ◽

Cd4 T Cell ◽

T Cell Tolerance ◽

Cell Tolerance

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

Journal of Experimental Medicine ◽

10.1084/jem.20011904 ◽

2002 ◽

Vol 195 (10) ◽

pp. 1349-1358 ◽

Cited By ~ 124

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.

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