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Article ; Online: Intraepithelial Lymphocytes of the Intestine.

Lockhart, Ainsley / Mucida, Daniel / Bilate, Angelina M

2024

Abstract: The intestinal epithelium, which segregates the highly stimulatory lumen from the underlying tissue, harbors one of the largest lymphocyte populations in the body, intestinal intraepithelial lymphocytes (IELs). IELs must balance tolerance, resistance, ... ...

Abstract	The intestinal epithelium, which segregates the highly stimulatory lumen from the underlying tissue, harbors one of the largest lymphocyte populations in the body, intestinal intraepithelial lymphocytes (IELs). IELs must balance tolerance, resistance, and tissue protection to maintain epithelial homeostasis and barrier integrity. This review discusses the ontogeny, environmental imprinting, T cell receptor (TCR) repertoire, and function of intestinal IELs. Despite distinct developmental pathways, IEL subsets share core traits including an epithelium-adapted profile, innate-like properties, cytotoxic potential, and limited TCR diversity. IELs also receive important developmental and functional cues through interactions with epithelial cells, microbiota, and dietary components. The restricted TCR diversity of IELs suggests that a limited set of intestinal antigens drives IEL responses, with potential functional consequences. Finally, IELs play a key role in promoting homeostatic immunity and epithelial barrier integrity but can become pathogenic upon dysregulation. Therefore, IELs represent intriguing but underexamined therapeutic targets for inflammatory diseases and cancer. Expected final online publication date for the
Language	English
Publishing date	2024-01-26
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	604953-9
ISSN	1545-3278 ; 0732-0582
ISSN (online)	1545-3278
ISSN	0732-0582
DOI	10.1146/annurev-immunol-090222-100246
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Article ; Online: Immunity to enteric viruses.

Lockhart, Ainsley / Mucida, Daniel / Parsa, Roham

Immunity

2022 Volume 55, Issue 5, Page(s) 800–818

Abstract: Pathogenic enteric viruses are a major cause of morbidity and mortality, particularly among children in developing countries. The host response to enteric viruses occurs primarily within the mucosa, where the intestinal immune system must balance ... ...

Abstract	Pathogenic enteric viruses are a major cause of morbidity and mortality, particularly among children in developing countries. The host response to enteric viruses occurs primarily within the mucosa, where the intestinal immune system must balance protection against pathogens with tissue protection and tolerance to harmless commensal bacteria and food. Here, we summarize current knowledge in natural immunity to enteric viruses, highlighting specialized features of the intestinal immune system. We further discuss how knowledge of intestinal anti-viral mechanisms can be translated into vaccine development with particular focus on immunization in the oral route. Research reveals that the intestine is a complex interface between enteric viruses and the host where environmental factors influence susceptibility and immunity to infection, while viral infections can have lasting implications for host health. A deeper mechanistic understanding of enteric anti-viral immunity with this broader context can ultimately lead to better vaccines for existing and emerging viruses.
MeSH term(s)	Antigens, Viral ; Child ; Enterovirus Infections ; Humans ; Immunity, Innate ; Intestinal Mucosa ; Intestines ; Vaccines ; Viruses
Chemical Substances	Antigens, Viral ; Vaccines
Language	English
Publishing date	2022-05-17
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2022.04.007
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Zs.A 4227: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Dietary protein shapes the profile and repertoire of intestinal CD4+ T cells.

Lockhart, Ainsley / Reed, Aubrey / Rezende de Castro, Tiago / Herman, Calvin / Campos Canesso, Maria Cecilia / Mucida, Daniel

The Journal of experimental medicine

2023 Volume 220, Issue 8

Abstract: The intestinal immune system must tolerate food antigens to avoid allergy, a process requiring CD4+ T cells. Combining antigenically defined diets with gnotobiotic models, we show that food and microbiota distinctly influence the profile and T cell ... ...

Abstract	The intestinal immune system must tolerate food antigens to avoid allergy, a process requiring CD4+ T cells. Combining antigenically defined diets with gnotobiotic models, we show that food and microbiota distinctly influence the profile and T cell receptor repertoire of intestinal CD4+ T cells. Independent of the microbiota, dietary proteins contributed to accumulation and clonal selection of antigen-experienced CD4+ T cells at the intestinal epithelium, imprinting a tissue-specialized transcriptional program including cytotoxic genes on both conventional and regulatory CD4+ T cells (Tregs). This steady state CD4+ T cell response to food was disrupted by inflammatory challenge, and protection against food allergy in this context was associated with Treg clonal expansion and decreased proinflammatory gene expression. Finally, we identified both steady-state epithelium-adapted CD4+ T cells and tolerance-induced Tregs that recognize dietary antigens, suggesting that both cell types may be critical for preventing inappropriate immune responses to food.
MeSH term(s)	CD4-Positive T-Lymphocytes ; Intestines ; T-Lymphocytes, Regulatory ; Immune Tolerance ; Antigens/metabolism ; Dietary Proteins/metabolism
Chemical Substances	Antigens ; Dietary Proteins
Language	English
Publishing date	2023-05-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20221816
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Article: Dietary protein shapes the profile and repertoire of intestinal CD4

Lockhart, Ainsley / Reed, Aubrey / de Castro, Tiago Rezende / Herman, Calvin / Canesso, Maria Cecilia Campos / Mucida, Daniel

bioRxiv : the preprint server for biology

2023

Abstract: The intestinal immune system must tolerate food antigens to avoid allergy, a process requiring ... ...

Abstract	The intestinal immune system must tolerate food antigens to avoid allergy, a process requiring CD4
Language	English
Publishing date	2023-04-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.11.536475
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: TCR-Vγδ usage distinguishes protumor from antitumor intestinal γδ T cell subsets.

Reis, Bernardo S / Darcy, Patrick W / Khan, Iasha Z / Moon, Christine S / Kornberg, Adam E / Schneider, Vanessa S / Alvarez, Yelina / Eleso, Olawale / Zhu, Caixia / Schernthanner, Marina / Lockhart, Ainsley / Reed, Aubrey / Bortolatto, Juliana / Castro, Tiago B R / Bilate, Angelina M / Grivennikov, Sergei / Han, Arnold S / Mucida, Daniel

Science (New York, N.Y.)

2022 Volume 377, Issue 6603, Page(s) 276–284

Abstract: γδ T cells represent a substantial fraction of intestinal lymphocytes at homeostasis, but they also constitute a major lymphocyte population infiltrating colorectal cancers (CRCs); however, their temporal contribution to CRC development or progression ... ...

Abstract	γδ T cells represent a substantial fraction of intestinal lymphocytes at homeostasis, but they also constitute a major lymphocyte population infiltrating colorectal cancers (CRCs); however, their temporal contribution to CRC development or progression remains unclear. Using human CRC samples and murine CRC models, we found that most γδ T cells in premalignant or nontumor colons exhibit cytotoxic markers, whereas tumor-infiltrating γδ T cells express a protumorigenic profile. These contrasting T cell profiles were associated with distinct T cell receptor (TCR)-Vγδ gene usage in both humans and mice. Longitudinal intersectional genetics and antibody-dependent strategies targeting murine γδ T cells enriched in the epithelium at steady state led to heightened tumor development, whereas targeting γδ subsets that accumulate during CRC resulted in reduced tumor growth. Our results uncover temporal pro- and antitumor roles for γδ T cell subsets.
MeSH term(s)	Animals ; Colorectal Neoplasms/immunology ; Colorectal Neoplasms/pathology ; Cytotoxicity, Immunologic ; Humans ; Intestines/immunology ; Intraepithelial Lymphocytes/immunology ; Mice ; Receptors, Antigen, T-Cell, gamma-delta/genetics ; Receptors, Antigen, T-Cell, gamma-delta/physiology
Chemical Substances	Receptors, Antigen, T-Cell, gamma-delta
Language	English
Publishing date	2022-07-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abj8695
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Zs.A 27: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 77: Show issues

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Article ; Online: Tunable dynamics of B cell selection in gut germinal centres.

Nowosad, Carla R / Mesin, Luka / Castro, Tiago B R / Wichmann, Christopher / Donaldson, Gregory P / Araki, Tatsuya / Schiepers, Ariën / Lockhart, Ainsley A K / Bilate, Angelina M / Mucida, Daniel / Victora, Gabriel D

Nature

2020 Volume 588, Issue 7837, Page(s) 321–326

Abstract: Germinal centres, the structures in which B cells evolve to produce antibodies with high affinity for various antigens, usually form transiently in lymphoid organs in response to infection or immunization. In lymphoid organs associated with the gut, ... ...

Abstract	Germinal centres, the structures in which B cells evolve to produce antibodies with high affinity for various antigens, usually form transiently in lymphoid organs in response to infection or immunization. In lymphoid organs associated with the gut, however, germinal centres are chronically present. These gut-associated germinal centres can support targeted antibody responses to gut infections and immunization
MeSH term(s)	Amino Acid Sequence ; Animals ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; Clonal Selection, Antigen-Mediated ; Clone Cells/cytology ; Clone Cells/immunology ; Female ; Gastrointestinal Microbiome/immunology ; Germ-Free Life ; Germinal Center/cytology ; Germinal Center/immunology ; Intestines/cytology ; Intestines/immunology ; Intestines/microbiology ; Kinetics ; Male ; Mice
Language	English
Publishing date	2020-10-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-020-2865-9
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 9: Show issues
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Article ; Online: NUSAP1 influences the DNA damage response by controlling BRCA1 protein levels.

Kotian, Shweta / Banerjee, Tapahsama / Lockhart, Ainsley / Huang, Kun / Catalyurek, Umit V / Parvin, Jeffrey D

Cancer biology & therapy

2014 Volume 15, Issue 5, Page(s) 533–543

Abstract: NUSAP1 has been reported to function in mitotic spindle assembly, chromosome segregation, and regulation of cytokinesis. In this study, we find that NUSAP1 has hitherto unknown functions in the key BRCA1-regulated pathways of double strand DNA break ... ...

Abstract	NUSAP1 has been reported to function in mitotic spindle assembly, chromosome segregation, and regulation of cytokinesis. In this study, we find that NUSAP1 has hitherto unknown functions in the key BRCA1-regulated pathways of double strand DNA break repair and centrosome duplication. Both these pathways are important for maintenance of genomic stability, and any defects in these pathways can cause tumorigenesis. Depletion of NUSAP1 from cells led to the suppression of double strand DNA break repair via the homologous recombination and single-strand annealing pathways. The presence of NUSAP1 was also found to be important for the control of centrosome numbers. We have found evidence that NUSAP1 plays a role in these processes through regulation of BRCA1 protein levels, and BRCA1 overexpression from a plasmid mitigates the defective phenotypes seen upon NUSAP1 depletion. We found that after NUSAP1 depletion there is a decrease in BRCA1 recruitment to ionizing radiation-induced foci. Results from this study reveal a novel association between BRCA1 and NUSAP1 and suggests a mechanism whereby NUSAP1 is involved in carcinogenesis.
MeSH term(s)	BRCA1 Protein/genetics ; BRCA1 Protein/metabolism ; Cell Line, Tumor ; Centrosome/metabolism ; DNA Damage/radiation effects ; DNA Repair ; DNA, Single-Stranded/metabolism ; G2 Phase Cell Cycle Checkpoints ; Homologous Recombination ; Humans ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; S Phase Cell Cycle Checkpoints
Chemical Substances	BRCA1 Protein ; DNA, Single-Stranded ; Microtubule-Associated Proteins ; NUSAP1 protein, human
Language	English
Publishing date	2014-02-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2146305-0
ISSN	1555-8576 ; 1538-4047
ISSN (online)	1555-8576
ISSN	1538-4047
DOI	10.4161/cbt.28019
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Article ; Online: Compartmentalized gut lymph node drainage dictates adaptive immune responses.

Esterházy, Daria / Canesso, Maria C C / Mesin, Luka / Muller, Paul A / de Castro, Tiago B R / Lockhart, Ainsley / ElJalby, Mahmoud / Faria, Ana M C / Mucida, Daniel

Nature

2019 Volume 569, Issue 7754, Page(s) 126–130

Abstract: The intestinal immune system has the challenging task of tolerating foreign nutrients and the commensal microbiome, while excluding or eliminating ingested pathogens. Failure of this balance leads to conditions such as inflammatory bowel diseases, food ... ...

Abstract	The intestinal immune system has the challenging task of tolerating foreign nutrients and the commensal microbiome, while excluding or eliminating ingested pathogens. Failure of this balance leads to conditions such as inflammatory bowel diseases, food allergies and invasive gastrointestinal infections
MeSH term(s)	Animals ; CD4 Antigens/metabolism ; Cell Differentiation ; Cell Movement ; Cell Polarity ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Duodenum/cytology ; Duodenum/immunology ; Duodenum/microbiology ; Female ; Lymph Nodes/cytology ; Lymph Nodes/immunology ; Lymph Nodes/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mouth/immunology ; Mouth/microbiology ; Rats ; Rats, Wistar ; Stromal Cells/immunology ; Stromal Cells/microbiology ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; T-Lymphocytes/microbiology
Chemical Substances	CD4 Antigens
Language	English
Publishing date	2019-04-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-019-1125-3
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Exploiting a host-commensal interaction to promote intestinal barrier function and enteric pathogen tolerance.

Pedicord, Virginia A / Lockhart, Ainsley A K / Rangan, Kavita J / Craig, Jeffrey W / Loschko, Jakob / Rogoz, Aneta / Hang, Howard C / Mucida, Daniel

Science immunology

2016 Volume 1, Issue 3

Abstract: Commensal intestinal bacteria can prevent pathogenic infection; however, limited knowledge of the mechanisms by which individual bacterial species contribute to pathogen resistance has restricted their potential for therapeutic application. Here, we ... ...

Abstract	Commensal intestinal bacteria can prevent pathogenic infection; however, limited knowledge of the mechanisms by which individual bacterial species contribute to pathogen resistance has restricted their potential for therapeutic application. Here, we examined how colonization of mice with a human commensal
Language	English
Publishing date	2016-09
Publishing country	United States
Document type	Journal Article
ISSN	2470-9468
ISSN	2470-9468
DOI	10.1126/sciimmunol.aai7732
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Article: Non-neutralizing Antibodies Alter the Course of HIV-1 Infection In Vivo

Horwitz, Joshua A / Bar-On, Yotam / Fera, Daniela / Gazumyan, Anna / Golijanin, Jovana / Lockhart, Ainsley A.K / Lorenzi, Julio C.C / Lu, Ching-Lan / Nogueira, Lilian / Nussenzweig, Michel C / Scheid, Johannes F / Seaman, Michael S / Zolla-Pazner, Susan

Cell. 2017 Aug. 10, v. 170

2017

Abstract: Non-neutralizing antibodies (nnAbs) to HIV-1 show little measurable activity in prevention or therapy in animal models yet were the only correlate of protection in the RV144 vaccine trial. To investigate the role of nnAbs on HIV-1 infection in vivo, we ... ...

Abstract	Non-neutralizing antibodies (nnAbs) to HIV-1 show little measurable activity in prevention or therapy in animal models yet were the only correlate of protection in the RV144 vaccine trial. To investigate the role of nnAbs on HIV-1 infection in vivo, we devised a replication-competent HIV-1 reporter virus that expresses a heterologous HA-tag on the surface of infected cells and virions. Anti-HA antibodies bind to, but do not neutralize, the reporter virus in vitro. However, anti-HA protects against infection in humanized mice and strongly selects for nnAb-resistant viruses in an entirely Fc-dependent manner. Similar results were also obtained with tier 2 HIV-1 viruses using a human anti-gp41 nnAb, 246D. While nnAbs are demonstrably less effective than broadly neutralizing antibodies (bNAbs) against HIV-1 in vitro and in vivo, the data show that nnAbs can protect against and alter the course of HIV-1 infection in vivo.[Display omitted]
Keywords	animal models ; HIV infections ; Human immunodeficiency virus 1 ; humans ; mice ; neutralization ; neutralizing antibodies ; therapeutics ; vaccines ; virion ; viruses
Language	English
Dates of publication	2017-0810
Size	p. 637-648.e10.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2017.06.048
Database	NAL-Catalogue (AGRICOLA)

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