scholarly journals Liver X receptors are required for thymic resilience and T cell output

2020 ◽  
Vol 217 (10) ◽  
Author(s):  
Christopher T. Chan ◽  
Ashley M. Fenn ◽  
Nina K. Harder ◽  
John E. Mindur ◽  
Cameron S. McAlpine ◽  
...  
Keyword(s):  
T Cell ◽  
Negative Selection ◽  
Lymphoid Organ ◽  
Thymic Epithelial Cells ◽  
Liver X Receptors ◽  
Cell Repertoire ◽  
Autoimmune Encephalomyelitis ◽  
X Receptors ◽  
And Function ◽  
Mutually Independent

The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)—a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity—critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαβ’s functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαβ for cholesterol efflux, thymic epithelial cells (TECs) use LXRαβ for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαβ protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαβ limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ governs T lymphocyte education and illuminate LXRαβ’s indispensable roles in adaptive immunity.

scholarly journals An essential role for gp39, the ligand for CD40, in thymic selection.

1995 ◽  
Vol 182 (5) ◽  
pp. 1377-1388 ◽  
Author(s):  
T M Foy ◽  
D M Page ◽  
T J Waldschmidt ◽  
A Schoneveld ◽  
J D Laman ◽  
...  
Keyword(s):  
T Cell ◽  
Negative Selection ◽  
Costimulatory Molecule ◽  
Immunohistochemical Analysis ◽  
Cell Receptor ◽  
Thymic Epithelial Cells ◽  
High Dose ◽  
Cell Repertoire ◽  
Endogenous Expression ◽  
Staphylococcus Enterotoxin B

The interactions between CD40 on B cells and its ligand gp39 on activated T helper cells are known to be essential for the development of thymus-dependent humoral immunity. However, CD40 is also functionally expressed on thymic epithelial cells and dendritic cells, suggesting that gp39-CD40 interactions may also play a role in thymic education, the process by which self-reactive cells are deleted from the T cell repertoire. Six systems of negative selection were studied for their reliance on gp39-CD40 interactions to mediate negative selection. In all cases, when the antigen/superantigen was endogenously expressed (in contrast to exogenously administered), negative selection was blocked by loss of gp39 function. Specifically, blockade of gp39-CD40 interactions prevented the deletion of thymocytes expressing V beta 3, V beta 11, and V beta 12, specificities normally deleted in BALB/c mice because of the endogenous expression of minor lymphocyte-stimulating determinants. Independent verification of a role of gp39 in negative selection was provided by studies in gp39-deficient mice where alterations in T cell receptor (TCR) V beta expression were also observed. Studies were also performed in the AND TCR transgenic (Tg) mice, which bear the V alpha 11, V beta 3 TCR and recognize both pigeon cytochrome c (PCC)/IEk and H-2As. Neonatal administration of anti-gp39 to AND TCR Tg mice that endogenously express H-2As or endogenously produce PCC prevented the deletion of TCR Tg T cells. In contrast, deletion mediated by high-dose PCC peptide antigen (administered exogenously) in AND TCR mice was unaltered by administration of anti-gp39. In addition, deletion by Staphylococcus enterotoxin B in conventional mice was also unaffected by anti-gp39 administration. gp39 expression was induced on thymocytes by mitogens or by antigen on TCR Tg thymocytes. Immunohistochemical analysis of B7-2 expression in the thymus indicated that, in the absence of gp39, B7-2 expression was substantially reduced. Taken together, these data suggest that gp39 may influence negative selection through the regulation of costimulatory molecule expression. Moreover, the data support the hypothesis that, for negative selection to some endogenously produced antigens, negative selection may be dependent on TCR engagement and costimulation.

scholarly journals The lysophosphatidylserine receptor GPR174 constrains regulatory T cell development and function

2015 ◽  
Vol 212 (7) ◽  
pp. 1011-1020 ◽  
Author(s):  
Michael J. Barnes ◽  
Chien-Ming Li ◽  
Ying Xu ◽  
Jinping An ◽  
Yong Huang ◽  
...  
Keyword(s):  
T Cell ◽  
Regulatory T Cell ◽  
Therapeutic Potential ◽  
Lymphoid Organ ◽  
Cell Generation ◽  
Autoimmune Encephalomyelitis ◽  
Cell Accumulation ◽  
And Function

Regulatory T cell (T reg cell) numbers and activities are tightly calibrated to maintain immune homeostasis, but the mechanisms involved are incompletely defined. Here, we report that the lysophosphatidylserine (LysoPS) receptor GPR174 is abundantly expressed in developing and mature T reg cells. In mice that lacked this X-linked gene, T reg cell generation in the thymus was intrinsically favored, and a higher fraction of peripheral T reg cells expressed CD103. LysoPS could act in vitro via GPR174 to suppress T cell proliferation and T reg cell generation. In vivo, LysoPS was detected in lymphoid organ and spinal cord tissues and was abundant in the colon. Gpr174−/Y mice were less susceptible to experimental autoimmune encephalomyelitis than wild-type mice, and GPR174 deficiency in T reg cells contributed to this phenotype. This study provides evidence that a bioactive lipid, LysoPS, negatively influences T reg cell accumulation and activity through GPR174. As such, GPR174 antagonists might have therapeutic potential for promoting immune regulation in the context of autoimmune disease.

scholarly journals The versatility of liver X receptors in T cell homeostasis: Location, location, location!

2021 ◽  
Vol 218 (4) ◽  
Author(s):  
Truong San Phan ◽  
Thomas Brunner
Keyword(s):  
T Cell ◽  
Nuclear Receptors ◽  
Target Cells ◽  
Liver X Receptors ◽  
T Cell Homeostasis ◽  
Specific Expression ◽  
Cell Homeostasis ◽  
Cell Type Specific Expression ◽  
X Receptors ◽  
And Function

Nuclear receptors control the transcriptional program of target cells and thereby their phenotype and activities. Two complementary studies by Micheals et al. (https://doi.org/10.1084/jem.20201311) and Chan et al. (https://doi.org/10.1084/jem.20200318) published in JEM uncover the cell type–specific expression and role of the nuclear receptors liver X receptors in the regulation of T cell homeostasis and function.

scholarly journals Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

2021 ◽  
Vol 9 (6) ◽  
pp. 1177
Author(s):  
Abdulaziz Alhazmi ◽  
Magloire Pandoua Nekoua ◽  
Hélène Michaux ◽  
Famara Sane ◽  
Aymen Halouani ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Viral Infections ◽  
Lymphoid Organ ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Coxsackievirus B4

The thymus gland is a primary lymphoid organ for T-cell development. Various viral infections can result in disturbance of thymic functions. Medullary thymic epithelial cells (mTECs) are important for the negative selection of self-reactive T-cells to ensure central tolerance. Insulin-like growth factor 2 (IGF2) is the dominant self-peptide of the insulin family expressed in mTECs and plays a crucial role in the intra-thymic programing of central tolerance to insulin-secreting islet β-cells. Coxsackievirus B4 (CVB4) can infect and persist in the thymus of humans and mice, thus hampering the T-cell maturation and differentiation process. The modulation of IGF2 expression and protein synthesis during a CVB4 infection has been observed in vitro and in vivo in mouse models. The effect of CVB4 infections on human and mouse fetal thymus has been studied in vitro. Moreover, following the inoculation of CVB4 in pregnant mice, the thymic function in the fetus and offspring was disturbed. A defect in the intra-thymic expression of self-peptides by mTECs may be triggered by CVB4. The effects of viral infections, especially CVB4 infection, on thymic cells and functions and their possible role in the pathogenesis of type 1 diabetes (T1D) are presented.

scholarly journals Age-Related Changes in Thymic Central Tolerance

2021 ◽  
Vol 12 ◽  
Author(s):  
Jayashree Srinivasan ◽  
Jessica N. Lancaster ◽  
Nandini Singarapu ◽  
Laura P. Hale ◽  
Lauren I. R. Ehrlich ◽  
...  
Keyword(s):  
T Cells ◽  
Negative Selection ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Adult Transition ◽  
Treg Function ◽  
Age Related ◽  
And Function ◽  
Antigen Presenting ◽  
Age Related Changes

Thymic epithelial cells (TECs) and hematopoietic antigen presenting cells (HAPCs) in the thymus microenvironment provide essential signals to self-reactive thymocytes that induce either negative selection or generation of regulatory T cells (Treg), both of which are required to establish and maintain central tolerance throughout life. HAPCs and TECs are comprised of multiple subsets that play distinct and overlapping roles in central tolerance. Changes that occur in the composition and function of TEC and HAPC subsets across the lifespan have potential consequences for central tolerance. In keeping with this possibility, there are age-associated changes in the cellular composition and function of T cells and Treg. This review summarizes changes in T cell and Treg function during the perinatal to adult transition and in the course of normal aging, and relates these changes to age-associated alterations in thymic HAPC and TEC subsets.

scholarly journals The Aire family expands

2019 ◽  
Vol 216 (5) ◽  
pp. 1010-1011
Author(s):  
Adrian Liston ◽  
James Dooley
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Lymph Nodes ◽  
Thymic Epithelial Cells ◽  
T Cell Tolerance ◽  
T Cell Repertoire ◽  
Cell Tolerance ◽  
Cell Repertoire

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.

scholarly journals Changes in Human Mucosal γδ T Cell Repertoire and Function Associated with the Disease Process in Inflammatory Bowel Disease

1997 ◽  
Vol 3 (3) ◽  
pp. 183-203 ◽  
Author(s):  
Laila D. McVay ◽  
Baiqing Li ◽  
Renée Biancaniello ◽  
Mary Anne Creighton ◽  
Dale Bachwich ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cell ◽  
Bowel Disease ◽  
Disease Process ◽  
T Cell Repertoire ◽  
Γδ T Cell ◽  
Cell Repertoire ◽  
Inflammatory Bowel ◽  
And Function

Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells

10.1038/71540 ◽  
2000 ◽  
Vol 6 (1) ◽  
pp. 56-61 ◽  
Author(s):  
Ludger Klein ◽  
Matthias Klugmann ◽  
Klaus-Armin Nave ◽  
V K Tuohy ◽  
Bruno Kyewski
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Splice Variant ◽  
Thymic Epithelial Cells ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Autoreactive T Cell
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