scholarly journals Classical MHC expression by DP thymocytes impairs the selection of non-classical MHC restricted innate-like T cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hristo Georgiev ◽  
Changwei Peng ◽  
Matthew A. Huggins ◽  
Stephen C. Jameson ◽  
Kristin A. Hogquist
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Cell Types ◽  
Inkt Cells ◽  
Mhc I ◽  
Mait Cells ◽  
Mhc Molecules ◽  
Mhc Ii ◽  
Different Cell Types ◽  
Selection Of

AbstractConventional T cells are selected by peptide-MHC expressed by cortical epithelial cells in the thymus, and not by cortical thymocytes themselves that do not express MHC I or MHC II. Instead, cortical thymocytes express non-peptide presenting MHC molecules like CD1d and MR1, and promote the selection of PLZF+ iNKT and MAIT cells, respectively. Here, we report an inducible class-I transactivator mouse that enables the expression of peptide presenting MHC I molecules in different cell types. We show that MHC I expression in DP thymocytes leads to expansion of peptide specific PLZF+ innate-like (PIL) T cells. Akin to iNKT cells, PIL T cells differentiate into three functional effector subsets in the thymus, and are dependent on SAP signaling. We demonstrate that PIL and NKT cells compete for a narrow niche, suggesting that the absence of peptide-MHC on DP thymocytes facilitates selection of non-peptide specific lymphocytes.

scholarly journals Reverse Signaling by MHC-I Molecules in Immune and Non-Immune Cell Types

2020 ◽  
Vol 11 ◽  
Author(s):  
Elke M. Muntjewerff ◽  
Luca D. Meesters ◽  
Geert van den Bogaart ◽  
Natalia H. Revelo
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Cell Types ◽  
Signaling Molecules ◽  
Target Cells ◽  
Class I Mhc ◽  
Mhc I ◽  
Reverse Signaling ◽  
Mhc Molecules

Major histocompatibility complex (MHC) molecules are well-known for their role in antigen (cross-) presentation, thereby functioning as key players in the communication between immune cells, for example dendritic cells (DCs) and T cells, or immune cells and their targets, such as T cells and virus-infected or tumor cells. However, much less appreciated is the fact that MHC molecules can also act as signaling receptors. In this process, here referred to as reverse MHC class I (MHC-I) signaling, ligation of MHC molecules can lead to signal-transduction and cell regulatory effects in the antigen presenting cell. In the case of MHC-I, reverse signaling can have several outcomes, including apoptosis, migration, induced or reduced proliferation and cytotoxicity towards target cells. Here, we provide an overview of studies showing the signaling pathways and cell outcomes upon MHC-I stimulation in various immune and non-immune cells. Signaling molecules like RAC-alpha serine/threonine-protein kinase (Akt1), extracellular signal-regulated kinases 1/2 (ERK1/2), and nuclear factor-κB (NF-κB) were common signaling molecules activated upon MHC-I ligation in multiple cell types. For endothelial and smooth muscle cells, the in vivo relevance of reverse MHC-I signaling has been established, namely in the context of adverse effects after tissue transplantation. For other cell types, the role of reverse MHC-I signaling is less clear, since aspects like the in vivo relevance, natural MHC-I ligands and the extended downstream pathways are not fully known.The existing evidence, however, suggests that reverse MHC-I signaling is involved in the regulation of the defense against bacterial and viral infections and against malignancies. Thereby, reverse MHC-I signaling is a potential target for therapies against viral and bacterial infections, cancer immunotherapies and management of organ transplantation outcomes.

PDGFRα-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 954-960 ◽  
Author(s):  
William E. Jenkinson ◽  
Simona W. Rossi ◽  
Sonia M. Parnell ◽  
Eric J. Jenkinson ◽  
Graham Anderson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Growth Factor Receptor ◽  
Thymic Epithelial Cells ◽  
Thymic Tissue ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Medullary Epithelial Cells ◽  
Selection Of

Abstract The thymus provides a specialized site for the production of T cells capable of recognizing foreign antigens in the context of self–major histocompatibility complex (MHC) molecules. During development, the thymus arises from an epithelial rudiment containing bipotent progenitors that differentiate into distinct cortical and medullary epithelial cells to regulate the maturation and selection of self-tolerant CD4+ and CD8+ T cells. In addition to their differentiation, thymic epithelial cells undergo cellular expansion to ensure that sufficient intrathymic cellular niches are available to support the large number of immature thymocytes required to form a self-tolerant T-cell pool. Thus, intrathymic T-cell production is intimately linked to the formation and availability of niches within thymic microenvironments. Here, we show the increase in intrathymic niches caused by the proliferation of the epithelium in the developing thymus is temporally regulated, and correlates with the presence of a population of fetal thymic mesenchyme defined by platelet-derived growth factor receptor α (PDGFRα) expression. Depletion of PDGFRα+ mesenchyme from embryonic thymi prior to their transplantation to ectopic sites results in the formation of functional yet hypoplastic thymic tissue. In summary, we highlight a specialized role for PDGFRα+ fetal mesenchyme in the thymus by determining availability of thymic niches through the regulation of thymic epithelial proliferation.

Luminal antigens access late endosomes of intestinal epithelial cells enriched in MHC I and MHC II molecules: in vivo study in Crohn's ileitis

2007 ◽  
Vol 293 (4) ◽  
pp. G798-G808 ◽  
Author(s):  
Gheorghe Hundorfean ◽  
Klaus-Peter Zimmer ◽  
Stephan Strobel ◽  
Andreas Gebert ◽  
Diether Ludwig ◽  
...  
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Antigen Processing ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Mhc I ◽  
Mhc Ii ◽  
Late Endosomes ◽  
Early Endosomes

In contrast to healthy conditions, intestinal epithelial cells (IECs) stimulate proinflammatory CD4+and CD8+T cells during Crohn's disease (CD). The underlying regulatory mechanisms remain unknown. Here we investigated the epithelial expression of major histocompatibility complex (MHC) I and MHC II and its interference with endocytic pathways, in vivo. During ileoscopy, ovalbumin (OVA) was sprayed onto ileal mucosa of CD patients (ileitis and remission) and controls. The epithelial traffic of OVA and MHC I/II pathways were studied in biopsies using fluorescence and electron microscopy. We found MHC I and MHC II to accumulate within multivesicular late endosomes (MVLE) of IECs. Faint labeling for these molecules was seen in early endosomes and lysosomes. MVLE were entered by OVA 10 min after exposure. Exosomes carrying MHC I, MHC II, and OVA were detected in intercellular spaces of the epithelium. OVA trafficking and labeling patterns for MHC I and MHC II in IECs showed no differences between CD patients and controls. Independent of inflammatory stimuli, MHC I and MHC II pathways intersect MVLE in IECs, which were efficiently targeted by luminal antigens. Similar to MHC II-enriched compartments in professional antigen presenting cells, these MVLE might be critically involved in MHC I- and MHC II-related antigen processing in IECs and the source of epithelial-released exosomes. The access of luminal antigens to MHC I in MVLE might indicate that the presentation of exogenous antigens by IECs must not be restricted to MHC II but might also occur as “cross-presentation” via MHC I to CD8+T cells.

scholarly journals Extraneous E-Cadherin Engages the Deterministic Process of Somatic Reprogramming through Modulating STAT3 and Erk1/2 Activity

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 284
Author(s):  
Yu-Hao Liu ◽  
Chien-Chang Chen ◽  
Yi-Jen Hsueh ◽  
Li-Man Hung ◽  
David Hui-Kang Ma ◽  
...  
Keyword(s):  
Stochastic Process ◽  
Molecular Mechanism ◽  
Activity Ratio ◽  
Cell Types ◽  
Deterministic Process ◽  
Modes Of Action ◽  
Molecular Events ◽  
Different Cell Types ◽  
Selection Of ◽  
E Cadherin

Although several modes of reprogramming have been reported in different cell types during iPSC induction, the molecular mechanism regarding the selection of different modes of action is still mostly unknown. The present study examined the molecular events that participate in the selection of such processes at the onset of somatic reprogramming. The activity of STAT3 versus that of Erk1/2 reversibly determines the reprogramming mode entered; a lower activity ratio favors the deterministic process and vice versa. Additionally, extraneous E-cadherin facilitates the early events of somatic reprogramming, potentially by stabilizing the LIF/gp130 and EGFR/ErbB2 complexes to promote entry into the deterministic process. Our current findings demonstrated that manipulating the pSTAT3/pErk1/2 activity ratio in the surrounding milieu can drive different modes of action toward either the deterministic or the stochastic process in the context of OSKM-mediated somatic reprogramming.

823 CD4 T cells are essential for an anti-tumor effect in a B78 murine melanoma tumor model

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A873-A873
Author(s):  
Arika Feils ◽  
Mackenzie Heck ◽  
Anna Hoefges ◽  
Peter Carlson ◽  
Luke Zangl ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Cd4 T Cells ◽  
Tumor Response ◽  
Immune Cell ◽  
Cd8 T Cell ◽  
Mhc I ◽  
Mhc Ii ◽  
Flow Cytometric

BackgroundMice bearing B78 melanoma tumors can be cured using an in situ vaccine (ISV) regimen that includes radiation (RT) together with immunocytokine (tumor-targeting mAb conjugated to IL-2). B78 melanoma cells, derived from B16 cells, express minimal to no MHC-I but express MHC-II upon IFN-g/TNF-a stimulation. Although B78 cells are primarily MHC-I-deficient, an increased CD8 T cell infiltration into the tumor microenvironment (TME) has been shown following ISV.1 To further investigate the potential role of specific immune cell lineages in the B78 anti-tumor response to ISV, immune subset depletion studies and flow cytometric analyses were performed.MethodsC57BL/6 mice bearing B78 tumors were depleted of immune cell subsets with mAbs (anti-CD4, anti-CD8, anti-NK1.1, or Rat IgG control) for 3 weeks during the course of treatment. Treatment groups included no treatment, RT (12 Gy), or ISV (RT D0 and immunocytokine D5-D9). 6 mice/group (repeated three times) were followed for survival/tumor growth, and flow cytometry studies included 4 mice/group, sacrificed on D8 and D13 following the start of ISV.ResultsMice depleted of CD4 T cells during the course of ISV showed a significant reduction of anti-tumor effect as compared to mice treated with ISV/Rat IgG (pConclusionsThese studies suggest that CD4 T cells are essential for an anti-tumor response in the B78 melanoma model. In vivo depletion data show that CD4 T cells, but not CD8 or NK cells, are required for a decrease in tumor growth via ISV. Flow cytometric analyses suggest an interplay between CD4 and CD8 T cells as indicated by a decrease in CD8/IFN-g expression following ISV in the absence of CD4 T cells. The role that MHC-I and MHC-II expression plays in this CD4/CD8 T cell anti-tumor response is under investigation. In future studies, B78 melanoma may serve as a critical syngeneic model for development of more effective immunotherapy treatment regimens.Ethics ApprovalAll animal experiments were performed in accordance with protocols approved by Animal Care and Use Committees of the University of Wisconsin-Madison.ReferenceMorris Z, Guy E, Francis D, et al. In situ tumor vaccination by combining local radiation and tumor-specific antibody or immunocytokine treatments. Cancer Res 2016;76(13):3929-3941.

Cultured epithelial cells derived from human foetal pancreas as a model for the study of cystic fibrosis: further analyses on the origins and nature of the cell types

1988 ◽  
Vol 90 (1) ◽  
pp. 73-77
Author(s):  
A. Harris ◽  
L. Coleman
Keyword(s):  
Cystic Fibrosis ◽  
Tissue Culture ◽  
Epithelial Cells ◽  
Culture System ◽  
Cultured Cells ◽  
Cell Types ◽  
Cultured Epithelial Cells ◽  
Different Cell Types ◽  
Foetal Pancreas

The establishment of a tissue-culture system for epithelial cells derived from human foetal pancreas has recently been reported. Further analyses have now been made on these cells in vitro, together with parallel investigation of the distribution of different cell types within the intact foetal pancreas. Results support the view that the cultured cells are ductal in origin and nature. Pancreatic epithelial cell cultures have also been established from foetuses with cystic fibrosis.

scholarly journals Human TCR-MHC coevolution after divergence from mice includes increased nontemplate-encoded CDR3 diversity

2017 ◽  
Vol 214 (11) ◽  
pp. 3417-3433 ◽  
Author(s):  
Xiaojing Chen ◽  
Lucia Poncette ◽  
Thomas Blankenstein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Mhc Molecules ◽  
Mhc Ii ◽  
Cdr3 Length ◽  
Tcr Repertoire ◽  
Cell Diversity ◽  
Antigen Presenting

For thymic selection and responses to pathogens, T cells interact through their αβ T cell receptor (TCR) with peptide–major histocompatibility complex (MHC) molecules on antigen-presenting cells. How the diverse TCRs interact with a multitude of MHC molecules is unresolved. It is also unclear how humans generate larger TCR repertoires than mice do. We compared the TCR repertoire of CD4 T cells selected from a single mouse or human MHC class II (MHC II) in mice containing the human TCR gene loci. Human MHC II yielded greater thymic output and a more diverse TCR repertoire. The complementarity determining region 3 (CDR3) length adjusted for different inherent V-segment affinities to MHC II. Humans evolved with greater nontemplate-encoded CDR3 diversity than did mice. Our data, which demonstrate human TCR–MHC coevolution after divergence from rodents, explain the greater T cell diversity in humans and suggest a mechanism for ensuring that any V–J gene combination can be selected by a single MHC II.

scholarly journals In Pursuit of Adult Progenitors of Thymic Epithelial Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Tatsuya Ishikawa ◽  
Nobuko Akiyama ◽  
Taishin Akiyama
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Adaptive Immune System ◽  
Thymic Epithelial Cells ◽  
Adaptive Immune ◽  
Peripheral T Cells ◽  
Robust Adaptive ◽  
Adult Thymus ◽  
Shed Light ◽  
Selection Of

Peripheral T cells capable of discriminating between self and non-self antigens are major components of a robust adaptive immune system. The development of self-tolerant T cells is orchestrated by thymic epithelial cells (TECs), which are localized in the thymic cortex (cortical TECs, cTECs) and medulla (medullary TECs, mTECs). cTECs and mTECs are essential for differentiation, proliferation, and positive and negative selection of thymocytes. Recent advances in single-cell RNA-sequencing technology have revealed a previously unknown degree of TEC heterogeneity, but we still lack a clear picture of the identity of TEC progenitors in the adult thymus. In this review, we describe both earlier and recent findings that shed light on features of these elusive adult progenitors in the context of tissue homeostasis, as well as recovery from stress-induced thymic atrophy.

scholarly journals Phenotypical and functional alteration of unconventional T cells in severe COVID-19 patients

2020 ◽  
Vol 217 (12) ◽  
Author(s):  
Youenn Jouan ◽  
Antoine Guillon ◽  
Loïc Gonzalez ◽  
Yonatan Perez ◽  
Chloé Boisseau ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Biology ◽  
Potential Contribution ◽  
Inkt Cells ◽  
Mait Cells ◽  
Phenotypic Alteration ◽  
T Cell Biology ◽  
Life Threatening ◽  
Regulatory Functions ◽  
Functional Alteration

COVID-19 includes lung infection ranging from mild pneumonia to life-threatening acute respiratory distress syndrome (ARDS). Dysregulated host immune response in the lung is a key feature in ARDS pathophysiology. However, cellular actors involved in COVID-19–driven ARDS are poorly understood. Here, in blood and airways of severe COVID-19 patients, we serially analyzed unconventional T cells, a heterogeneous class of T lymphocytes (MAIT, γδT, and iNKT cells) with potent antimicrobial and regulatory functions. Circulating unconventional T cells of COVID-19 patients presented with a profound and persistent phenotypic alteration. In the airways, highly activated unconventional T cells were detected, suggesting a potential contribution in the regulation of local inflammation. Finally, expression of the CD69 activation marker on blood iNKT and MAIT cells of COVID-19 patients on admission was predictive of clinical course and disease severity. Thus, COVID-19 patients present with an altered unconventional T cell biology, and further investigations will be required to precisely assess their functions during SARS–CoV-2–driven ARDS.

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