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Autophagy-related protein Vps34 controls the homeostasis and function of antigen cross-presenting CD8α dendritic cells.
Parekh VV, Pabbisetty SK, Wu L, Sebzda E, Martinez J, Zhang J, Van Kaer L
(2017) Proc Natl Acad Sci U S A 114: E6371-E6380
MeSH Terms: Animals, Antigen Presentation, Autophagy, Autophagy-Related Proteins, CD8 Antigens, CD8-Positive T-Lymphocytes, Cells, Cultured, Class III Phosphatidylinositol 3-Kinases, Cross-Priming, Cytokines, Dendritic Cells, Endocytosis, Histocompatibility Antigens Class I, Melanoma, Experimental, Membrane Proteins, Mice, Mice, Knockout, Phagocytosis
Show Abstract · Added March 26, 2019
The class III PI3K Vacuolar protein sorting 34 (Vps34) plays a role in both canonical and noncanonical autophagy, key processes that control the presentation of antigens by dendritic cells (DCs) to naive T lymphocytes. We generated DC-specific -deficient mice to assess the contribution of Vps34 to DC functions. We found that DCs from these animals have a partially activated phenotype, spontaneously produce cytokines, and exhibit enhanced activity of the classic MHC class I and class II antigen-presentation pathways. Surprisingly, these animals displayed a defect in the homeostatic maintenance of splenic CD8α DCs and in the capacity of these cells to cross-present cell corpse-associated antigens to MHC class I-restricted T cells, a property that was associated with defective expression of the T-cell Ig mucin (TIM)-4 receptor. Importantly, mice deficient in the Vps34-associated protein Rubicon, which is critical for a noncanonical form of autophagy called "Light-chain 3 (LC3)-associated phagocytosis" (LAP), lacked such defects. Finally, consistent with their defect in the cross-presentation of apoptotic cells, DC-specific -deficient animals developed increased metastases in response to challenge with B16 melanoma cells. Collectively, our studies have revealed a critical role of Vps34 in the regulation of CD8α DC homeostasis and in the capacity of these cells to process and present antigens associated with apoptotic cells to MHC class I-restricted T cells. Our findings also have important implications for the development of small-molecule inhibitors of Vps34 for therapeutic purposes.
0 Communities
1 Members
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MeSH Terms
Histone Deacetylase 3 Is Required for Efficient T Cell Development.
Stengel KR, Zhao Y, Klus NJ, Kaiser JF, Gordy LE, Joyce S, Hiebert SW, Summers AR
(2015) Mol Cell Biol 35: 3854-65
MeSH Terms: Animals, CD4 Antigens, CD4-Positive T-Lymphocytes, CD8 Antigens, CD8-Positive T-Lymphocytes, Cell Differentiation, Gene Deletion, Gene Expression Regulation, Developmental, Histone Deacetylases, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Proto-Oncogene Proteins c-bcl-2, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, bcl-X Protein
Show Abstract · Added September 28, 2015
Hdac3 is a key target for Hdac inhibitors that are efficacious in cutaneous T cell lymphoma. Moreover, the regulation of chromatin structure is critical as thymocytes transition from an immature cell with open chromatin to a mature T cell with tightly condensed chromatin. To define the phenotypes controlled by Hdac3 during T cell development, we conditionally deleted Hdac3 using the Lck-Cre transgene. This strategy inactivated Hdac3 in the double-negative stages of thymocyte development and caused a significant impairment at the CD8 immature single-positive (ISP) stage and the CD4/CD8 double-positive stage, with few mature CD4(+) or CD8(+) single-positive cells being produced. When Hdac3(-/-) mice were crossed with Bcl-xL-, Bcl2-, or TCRβ-expressing transgenic mice, a modest level of complementation was found. However, when the null mice were crossed with mice expressing a fully rearranged T cell receptor αβ transgene, normal levels of CD4 single-positive cells were produced. Thus, Hdac3 is required for the efficient transit from double-negative stage 4 through positive selection.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
1 Communities
2 Members
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18 MeSH Terms
iCD8α cells: living at the edge of the intestinal immune system.
Olivares-Villagómez D, Van Kaer L
(2015) Oncotarget 6: 19964-5
MeSH Terms: Animals, CD8 Antigens, Humans, Immunity, Mucosal, Intestinal Mucosa, Mice
Added September 28, 2015
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2 Members
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6 MeSH Terms
Oligoclonal CD8+ T cells play a critical role in the development of hypertension.
Trott DW, Thabet SR, Kirabo A, Saleh MA, Itani H, Norlander AE, Wu J, Goldstein A, Arendshorst WJ, Madhur MS, Chen W, Li CI, Shyr Y, Harrison DG
(2014) Hypertension 64: 1108-15
MeSH Terms: Adaptive Immunity, Angiotensin II, Animals, CD4 Antigens, CD4-Positive T-Lymphocytes, CD8 Antigens, CD8-Positive T-Lymphocytes, Disease Models, Animal, Endothelium, Vascular, Homeodomain Proteins, Hypertension, Kidney, Major Histocompatibility Complex, Male, Mice, Mice, Knockout, Oligoclonal Bands, Vascular Remodeling
Show Abstract · Added March 31, 2015
Recent studies have emphasized a role of adaptive immunity, and particularly T cells, in the genesis of hypertension. We sought to determine the T-cell subtypes that contribute to hypertension and renal inflammation in angiotensin II-induced hypertension. Using T-cell receptor spectratyping to examine T-cell receptor usage, we demonstrated that CD8(+) cells, but not CD4(+) cells, in the kidney exhibited altered T-cell receptor transcript lengths in Vβ3, 8.1, and 17 families in response to angiotensin II-induced hypertension. Clonality was not observed in other organs. The hypertension caused by angiotensin II in CD4(-/-) and MHCII(-/-) mice was similar to that observed in wild-type mice, whereas CD8(-/-) mice and OT1xRAG-1(-/-) mice, which have only 1 T-cell receptor, exhibited a blunted hypertensive response to angiotensin II. Adoptive transfer of pan T cells and CD8(+) T cells but not CD4(+)/CD25(-) cells conferred hypertension to RAG-1(-/-) mice. In contrast, transfer of CD4(+)/CD25(+) cells to wild-type mice receiving angiotensin II decreased blood pressure. Mice treated with angiotensin II exhibited increased numbers of kidney CD4(+) and CD8(+) T cells. In response to a sodium/volume challenge, wild-type and CD4(-/-) mice infused with angiotensin II retained water and sodium, whereas CD8(-/-) mice did not. CD8(-/-) mice were also protected against angiotensin-induced endothelial dysfunction and vascular remodeling in the kidney. These data suggest that in the development of hypertension, an oligoclonal population of CD8(+) cells accumulates in the kidney and likely contributes to hypertension by contributing to sodium and volume retention and vascular rarefaction.
© 2014 American Heart Association, Inc.
2 Communities
2 Members
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18 MeSH Terms
CD8αα⁺ innate-type lymphocytes in the intestinal epithelium mediate mucosal immunity.
Van Kaer L, Algood HMS, Singh K, Parekh VV, Greer MJ, Piazuelo MB, Weitkamp JH, Matta P, Chaturvedi R, Wilson KT, Olivares-Villagómez D
(2014) Immunity 41: 451-464
MeSH Terms: Animals, Antigen Presentation, CD8 Antigens, Citrobacter rodentium, Cytochalasin D, Enterocolitis, Necrotizing, Helicobacter pylori, Histocompatibility Antigens Class I, Humans, Immunity, Mucosal, Inhibitor of Differentiation Protein 2, Interleukin Receptor Common gamma Subunit, Interleukin-15, Interleukin-2, Interleukin-7, Intestinal Mucosa, Lymphocyte Activation, Lymphocytes, Mice, Mice, Inbred C57BL, Mice, Knockout, Phagocytosis
Show Abstract · Added January 20, 2015
Innate immune responses are critical for mucosal immunity. Here we describe an innate lymphocyte population, iCD8α cells, characterized by expression of CD8α homodimers. iCD8α cells exhibit innate functional characteristics such as the capacity to engulf and kill bacteria. Development of iCD8α cells depends on expression of interleukin-2 receptor γ chain (IL-2Rγc), IL-15, and the major histocompatibility complex (MHC) class Ib protein H2-T3, also known as the thymus leukemia antigen or TL. While lineage tracking experiments indicated that iCD8α cells have a lymphoid origin, their development was independent of the transcriptional suppressor Id2, suggesting that these cells do not belong to the family of innate lymphoid cells. Finally, we identified cells with a similar phenotype in humans, which were profoundly depleted in newborns with necrotizing enterocolitis. These findings suggest a critical role of iCD8α cells in immune responses associated with the intestinal epithelium.
Copyright © 2014 Elsevier Inc. All rights reserved.
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5 Members
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22 MeSH Terms
Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase.
Wu J, Thabet SR, Kirabo A, Trott DW, Saleh MA, Xiao L, Madhur MS, Chen W, Harrison DG
(2014) Circ Res 114: 616-25
MeSH Terms: Adoptive Transfer, Angiotensin II, Animals, Aortic Diseases, CD4 Antigens, CD8 Antigens, Cells, Cultured, Collagen, Disease Models, Animal, Elastin, Fibroblasts, Homeodomain Proteins, Hypertension, Inflammation, Interleukin-17, Male, Mice, Mice, Knockout, Stress, Mechanical, T-Lymphocytes, Vascular Stiffness, Vasculitis, Vasoconstrictor Agents, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added July 21, 2014
RATIONALE - Aortic stiffening commonly occurs in hypertension and further elevates systolic pressure. Hypertension is also associated with vascular inflammation and increased mechanical stretch. The interplay between inflammation, mechanical stretch, and aortic stiffening in hypertension remains undefined.
OBJECTIVE - Our aim was to determine the role of inflammation and mechanical stretch in aortic stiffening.
METHODS AND RESULTS - Chronic angiotensin II infusion caused marked aortic adventitial collagen deposition, as quantified by Masson trichrome blue staining and biochemically by hydroxyproline content, in wild-type but not in recombination activating gene-1-deficient mice. Aortic compliance, defined by ex vivo measurements of stress-strain curves, was reduced by chronic angiotensin II infusion in wild-type mice (P<0.01) but not in recombination activating gene-1-deficient mice (P<0.05). Adoptive transfer of T-cells to recombination activating gene-1-deficient mice restored aortic collagen deposition and stiffness to values observed in wild-type mice. Mice lacking the T-cell-derived cytokine interleukin 17a were also protected against aortic stiffening. In additional studies, we found that blood pressure normalization by treatment with hydralazine and hydrochlorothiazide prevented angiotensin II-induced vascular T-cell infiltration, aortic stiffening, and collagen deposition. Finally, we found that mechanical stretch induces the expression of collagen 1α1, 3α1, and 5a1 in cultured aortic fibroblasts in a p38 mitogen-activated protein kinase-dependent fashion, and that inhibition of p38 prevented angiotensin II-induced aortic stiffening in vivo. Interleukin 17a also induced collagen 3a1 expression via the activation of p38 mitogen-activated protein kinase.
CONCLUSIONS - Our data define a pathway in which inflammation and mechanical stretch lead to vascular inflammation that promotes collagen deposition. The resultant increase in aortic stiffness likely further worsens systolic hypertension and its attendant end-organ damage.
2 Communities
3 Members
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24 MeSH Terms
In vitro induction of regulatory CD4+CD8α+ T cells by TGF-β, IL-7 and IFN-γ.
Van Kaer L, Rabacal WA, Scott Algood HM, Parekh VV, Olivares-Villagómez D
(2013) PLoS One 8: e67821
MeSH Terms: Adoptive Transfer, Animals, Antigens, CD, Antigens, Differentiation, CD4 Antigens, CD8 Antigens, CTLA-4 Antigen, Cell Differentiation, Cell Lineage, Core Binding Factor Alpha 3 Subunit, Cytokines, Immunophenotyping, Interferon-gamma, Interleukin-7, Intestinal Mucosa, Mice, Mice, Knockout, NK Cell Lectin-Like Receptor Subfamily K, Programmed Cell Death 1 Receptor, T-Lymphocytes, Regulatory, Transforming Growth Factor beta, Vitamin D
Show Abstract · Added March 7, 2014
In vitro CD4(+) T cell differentiation systems have made important contributions to understanding the mechanisms underlying the differentiation of naive CD4(+) T cells into effector cells with distinct biological functions. Mature CD4(+) T cells expressing CD8αα homodimers are primarily found in the intestinal mucosa of men and mice, and to a lesser extent in other tissues such as peripheral blood. Although CD4(+)CD8α(+) T cells are easily identified, very little is known about their development and immunological functions. It has been reported, however, that CD4(+)CD8α(+) T cells possess regulatory properties. In this report, we present a novel in vitro differentiation system where CD4(+) T cells are stimulated to become CD4(+)CD8α(+) T cells in the presence of TGF-β, IL-7 and IFN-γ, resulting in cells with very similar features as CD4(+)CD8α(+) intraepithelial lymphocytes. This novel in vitro differentiation culture should provide a powerful and tractable tool for dissecting the differentiation and biological functions of CD4(+)CD8α(+) T cells.
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3 Members
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22 MeSH Terms
Mucosal memory CD8⁺ T cells are selected in the periphery by an MHC class I molecule.
Huang Y, Park Y, Wang-Zhu Y, Larange A, Arens R, Bernardo I, Olivares-Villagómez D, Herndler-Brandstetter D, Abraham N, Grubeck-Loebenstein B, Schoenberger SP, Van Kaer L, Kronenberg M, Teitell MA, Cheroutre H
(2011) Nat Immunol 12: 1086-95
MeSH Terms: Animals, Antigens, CD8 Antigens, Cell Differentiation, Clonal Selection, Antigen-Mediated, Dendritic Cells, Immunity, Mucosal, Immunologic Memory, Listeriosis, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Precursor Cells, T-Lymphoid, T-Lymphocytes, Transgenes
Show Abstract · Added March 20, 2014
The presence of immune memory at pathogen-entry sites is a prerequisite for protection. Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood. Here we show that the nonclassical major histocompatibility complex (MHC) class I molecule thymus leukemia antigen (TL), induced on dendritic cells interacting with CD8αα on activated CD8αβ(+) T cells, mediated affinity-based selection of memory precursor cells. Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αβ(+) memory T cells. The memory process driven by TL and CD8αα was essential for the generation of CD8αβ(+) memory T cells in the intestine and the accumulation of highly antigen-sensitive CD8αβ(+) memory T cells that form the first line of defense at the largest entry port for pathogens.
0 Communities
2 Members
0 Resources
17 MeSH Terms
GSK3-mediated instability of tubulin polymers is responsible for the failure of immature CD4+CD8+ thymocytes to polarize their MTOC in response to TCR stimulation.
Cunningham NR, Hinchcliff EM, Kutyavin VI, Beck T, Reid WA, Punt JA
(2011) Int Immunol 23: 693-700
MeSH Terms: Aminophenols, Animals, Blotting, Western, CD4 Antigens, CD8 Antigens, Cell Differentiation, Enzyme Inhibitors, Female, Flow Cytometry, Gene Expression Regulation, Developmental, Glycogen Synthase Kinase 3, Lymphocyte Activation, Maleimides, Mice, Mice, Inbred C57BL, Microtubule-Organizing Center, Microtubules, Polymerization, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Thymocytes, Tubulin
Show Abstract · Added January 11, 2016
Although mature T cells divide and differentiate when they receive strong TCR stimulation, most immature CD4+CD8+ thymocytes die. The molecular basis for this marked difference in response is not known. Observations that TCR-stimulated CD4+CD8+ thymocytes fail to polarize their microtubule-organizing center (MTOC), one of the first events that occurs upon antigen activation of mature T cells, suggests that TCR signaling routes in immature and mature T cells diverge early and upstream of MTOC polarization. To better understand the source of the divergence, we examined the molecular basis for the difference in TCR-mediated MTOC polarization. We show that unstable microtubules are a feature of immature murine CD4+CD8+ thymocytes, which also exhibit higher levels of glycogen synthase kinase 3 (GSK3) activity, a known inhibitor of microtubule stability. Importantly, CD4+CD8+ thymocytes gained the ability to polarize their MTOC in response to TCR signals when GSK3 activity was inhibited. GSK3 inhibition also abrogated TCR-mediated apoptosis of immature thymocytes. Together, our results suggest that a developmentally regulated difference in GSK3 activity has a major influence on immature CD4+CD8+ thymocyte versus mature T-cell responses to TCR stimulation.
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1 Members
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23 MeSH Terms
TL and CD8αα: Enigmatic partners in mucosal immunity.
Olivares-Villagómez D, Van Kaer L
(2010) Immunol Lett 134: 1-6
MeSH Terms: Animals, CD8 Antigens, Humans, Immunity, Mucosal, Inflammatory Bowel Diseases, Intestinal Mucosa, Lymphocytes, Membrane Glycoproteins, Models, Immunological, Protein Binding
Show Abstract · Added March 20, 2014
The intestinal mucosa represents a large surface area that is in contact with an immense antigenic load. The immune system associated with the intestinal mucosa needs to distinguish between innocuous food antigens, commensal microorganisms, and pathogenic microorganisms, without triggering an exaggerated immune response that may lead to excessive inflammation and/or development of inflammatory bowel disease. The thymus leukemia (TL) antigen and CD8αα are interacting surface molecules that are expressed at the frontline of the mucosal immune system: TL is expressed in intestinal epithelial cells (IEC) whereas CD8αα is expressed in lymphocytes, known as intraepithelial lymphocytes, that reside in between the IEC. In this review we discuss the significance of the interaction between TL and CD8αα in mucosal immunity during health and disease.
Copyright © 2010 Elsevier B.V. All rights reserved.
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2 Members
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10 MeSH Terms