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1.
Front Immunol ; 14: 1250316, 2023.
Article in English | MEDLINE | ID: mdl-38022509

ABSTRACT

MHC-E restricted CD8 T cells show promise in vaccine settings, but their development and specificity remain poorly understood. Here we focus on a CD8 T cell population reactive to a self-peptide (FL9) bound to mouse MHC-E (Qa-1b) that is presented in response to loss of the MHC I processing enzyme ERAAP, termed QFL T cells. We find that mature QFL thymocytes are predominantly CD8αß+CD4-, show signs of agonist selection, and give rise to both CD8αα and CD8αß intraepithelial lymphocytes (IEL), as well as memory phenotype CD8αß T cells. QFL T cells require the MHC I subunit ß-2 microglobulin (ß2m), but do not require Qa1b or classical MHC I for positive selection. However, QFL thymocytes do require Qa1b for agonist selection and full functionality. Our data highlight the relaxed requirements for positive selection of an MHC-E restricted T cell population and suggest a CD8αß+CD4- pathway for development of CD8αα IELs.


Subject(s)
CD8-Positive T-Lymphocytes , Receptors, Antigen, T-Cell, alpha-beta , Animals , Mice , Peptides/metabolism , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Thymocytes/metabolism , Genes, MHC Class II
2.
Cell Rep ; 38(3): 110266, 2022 01 18.
Article in English | MEDLINE | ID: mdl-35045305

ABSTRACT

Production of effector CD8+ T cells during persistent infection requires a stable pool of stem-like cells that can give rise to effector cells via a proliferative intermediate population. In infection models marked by T cell exhaustion, this process can be transiently induced by checkpoint blockade but occurs spontaneously in mice chronically infected with the protozoan intracellular parasite Toxoplasma gondii. We observe distinct locations for parasite-specific T cell subsets, implying a link between differentiation and anatomical niches in the spleen. Loss of the chemokine receptor CXCR3 on T cells does not prevent white pulp-to-red pulp migration but reduces interactions with CXCR3 ligand-producing dendritic cells (DCs) and impairs memory-to-intermediate transition, leading to a buildup of memory T cells in the red pulp. Thus, CXCR3 increases T cell exposure to differentiation-inducing signals during red pulp migration, providing a dynamic mechanism for modulating effector differentiation in response to environmental signals.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cell Differentiation/immunology , Dendritic Cells/immunology , Lymphoid Progenitor Cells/immunology , Receptors, CXCR3/immunology , Spleen/immunology , Animals , Mice , Persistent Infection/immunology , Toxoplasmosis, Animal/immunology
3.
Mucosal Immunol ; 14(1): 68-79, 2021 01.
Article in English | MEDLINE | ID: mdl-32483197

ABSTRACT

Thymocytes bearing αß T cell receptors (TCRαß) with high affinity for self-peptide-MHC complexes undergo negative selection or are diverted to alternate T cell lineages, a process termed agonist selection. Among thymocytes bearing TCRs restricted to MHC class I, agonist selection can lead to the development of precursors that can home to the gut and give rise to CD8αα-expressing intraepithelial lymphocytes (CD8αα IELs). The factors that influence the choice between negative selection versus CD8αα IEL development remain largely unknown. Using a synchronized thymic tissue slice model that supports both negative selection and CD8αα IEL development, we show that the affinity threshold for CD8αα IEL development is higher than for negative selection. We also investigate the impact of peptide presenting cells and cytokines, and the migration patterns associated with these alternative cell fates. Our data highlight the roles of TCR affinity and the thymic microenvironments on T cell fate.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Clonal Selection, Antigen-Mediated , Intraepithelial Lymphocytes/immunology , Intraepithelial Lymphocytes/metabolism , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Thymus Gland/immunology , Thymus Gland/metabolism , CD8-Positive T-Lymphocytes/cytology , Cellular Microenvironment , Clonal Selection, Antigen-Mediated/genetics , Clonal Selection, Antigen-Mediated/immunology , Histocompatibility Antigens/chemistry , Histocompatibility Antigens/genetics , Histocompatibility Antigens/immunology , Intraepithelial Lymphocytes/cytology , Peptides/immunology , Thymus Gland/cytology
5.
Elife ; 82019 12 23.
Article in English | MEDLINE | ID: mdl-31868579

ABSTRACT

Autoreactive thymocytes are eliminated during negative selection in the thymus, a process important for establishing self-tolerance. Thymic phagocytes serve to remove dead thymocytes, but whether they play additional roles during negative selection remains unclear. Here, using a murine thymic slice model in which thymocytes undergo negative selection in situ, we demonstrate that phagocytosis promotes negative selection, and provide evidence for the escape of autoreactive CD8 T cells to the periphery when phagocytosis in the thymus is impaired. We also show that negative selection is more efficient when the phagocyte also presents the negative selecting peptide. Our findings support a model for negative selection in which the death process initiated following strong TCR signaling is facilitated by phagocytosis. Thus, the phagocytic capability of cells that present self-peptides is a key determinant of thymocyte fate.


Subject(s)
Cell Death , Lymphocyte Activation , Phagocytosis/physiology , Thymocytes/metabolism , Animals , Antigen Presentation , Bone Marrow Cells , CD8-Positive T-Lymphocytes/immunology , DNA-Binding Proteins/genetics , Homeodomain Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Animal , Peptides/metabolism , Receptors, Antigen, T-Cell/metabolism , Self Tolerance , Signal Transduction , Thymus Gland/immunology
6.
Immunity ; 45(1): 159-71, 2016 07 19.
Article in English | MEDLINE | ID: mdl-27421704

ABSTRACT

Highly functional CD8(+) effector T (Teff) cells can persist in large numbers during controlled persistent infections, as exemplified by rare HIV-infected individuals who control the virus. Here we examined the cellular mechanisms that maintain ongoing T effector responses using a mouse model for persistent Toxoplasma gondii infection. In mice expressing the protective MHC-I molecule, H-2L(d), a dominant T effector response against a single parasite antigen was maintained without a contraction phase, correlating with ongoing presentation of the dominant antigen. Large numbers of short-lived Teff cells were continuously produced via a proliferative, antigen-dependent intermediate (Tint) population with a memory-effector hybrid phenotype. During an acute, resolved infection, decreasing antigen load correlated with a sharp drop in the Tint cell population and subsequent loss of the ongoing effector response. Vaccination approaches aimed at the development of Tint populations might prove effective against pathogens that lead to chronic infection.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cell Differentiation , Lymphocyte Subsets/immunology , Toxoplasma/immunology , Toxoplasmosis/immunology , Animals , Antigen Presentation , Antigens, Protozoan/immunology , Antigens, Protozoan/metabolism , CD8-Positive T-Lymphocytes/parasitology , Cell Proliferation , Cells, Cultured , Chronic Disease , Cytotoxicity, Immunologic , Histocompatibility Antigens Class I/metabolism , Immunodominant Epitopes/immunology , Immunodominant Epitopes/metabolism , Immunologic Memory , Lymphocyte Subsets/parasitology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Antigen, T-Cell/genetics
7.
Nat Immunol ; 16(6): 635-41, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25939026

ABSTRACT

The thymic production of regulatory T cells (Treg cells) requires interleukin 2 (IL-2) and agonist T cell antigen receptor (TCR) ligands and is controlled by competition for a limited developmental niche, but the thymic sources of IL-2 and the factors that limit access to the niche are poorly understood. Here we found that IL-2 produced by antigen-bearing dendritic cells (DCs) had a key role in Treg cell development and that existing Treg cells limited new development of Treg cells by competing for IL-2. Our data suggest that antigen-presenting cells (APCs) that can provide both IL-2 and a TCR ligand constitute the thymic niche and that competition by existing Treg cells for a limited supply of IL-2 provides negative feedback for new production of Treg cells.


Subject(s)
Dendritic Cells/physiology , Interleukin-2/immunology , Receptors, Antigen, T-Cell/agonists , T-Lymphocytes, Regulatory/physiology , Thymus Gland/immunology , Animals , Antigen Presentation , Antigens/immunology , Cell Differentiation , Cell Line , Cellular Microenvironment , Feedback, Physiological , Interleukin-2/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic
8.
Immunol Cell Biol ; 92(10): 872-81, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25155465

ABSTRACT

The classic anti-viral cytokine interferon (IFN)-ß can be induced during parasitic infection, but relatively little is know about the cell types and signaling pathways involved. Here we show that inflammatory monocytes (IMs), but not neutrophils, produce IFN-ß in response to T. gondii infection. This difference correlated with the mode of parasite entry into host cells, with phagocytic uptake predominating in IMs and active invasion predominating in neutrophils. We also show that expression of IFN-ß requires phagocytic uptake of the parasite by IMs, and signaling through Toll-like receptors (TLRs) and MyD88. Finally, we show that IMs are major producers of IFN-ß in mesenteric lymph nodes following in vivo oral infection of mice, and mice lacking the receptor for type I IFN-1 show higher parasite loads and reduced survival. Our data reveal a TLR and internalization-dependent pathway in IMs for IFN-ß induction to a non-viral pathogen.


Subject(s)
Interferon-beta/biosynthesis , Monocytes/immunology , Toll-Like Receptors/metabolism , Toxoplasmosis, Animal/immunology , Animals , Immunity, Innate , Mice , Mice, Knockout , Myeloid Differentiation Factor 88/metabolism , Neutrophils/immunology , Signal Transduction , Toxoplasma/immunology , Toxoplasmosis, Animal/parasitology
9.
Cell Rep ; 7(5): 1716-1728, 2014 Jun 12.
Article in English | MEDLINE | ID: mdl-24857659

ABSTRACT

CD8 T cells play a key role in defense against the intracellular parasite Toxoplasma, but why certain CD8 responses are more potent than others is not well understood. Here, we describe a parasite antigen, ROP5, that elicits a CD8 T cell response in genetically susceptible mice. ROP5 is secreted via parasite organelles termed rhoptries that are injected directly into host cells during invasion, whereas the protective, dense-granule antigen GRA6 is constitutively secreted into the parasitophorous vacuole. Transgenic parasites in which the ROP5 antigenic epitope was targeted for secretion through dense granules led to enhanced CD8 T cell responses, whereas targeting the GRA6 epitope to rhoptries led to reduced CD8 responses. CD8 T cell responses to the dense-granule-targeted ROP5 epitope resulted in reduced parasite load in the brain. These data suggest that the mode of secretion affects the efficacy of parasite-specific CD8 T cell responses.


Subject(s)
Antigens, Protozoan/immunology , CD8-Positive T-Lymphocytes/immunology , Protozoan Proteins/immunology , Secretory Pathway , Toxoplasma/metabolism , Amino Acid Sequence , Animals , Antigens, Protozoan/chemistry , Epitopes/chemistry , Epitopes/immunology , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Molecular Sequence Data , Protozoan Proteins/chemistry , Toxoplasma/immunology
10.
Proc Natl Acad Sci U S A ; 110(21): E1913-22, 2013 May 21.
Article in English | MEDLINE | ID: mdl-23650399

ABSTRACT

Toxoplasma gondii infection occurs through the oral route, but we lack important information about how the parasite interacts with the host immune system in the intestine. We used two-photon laser-scanning microscopy in conjunction with a mouse model of oral T. gondii infection to address this issue. T. gondii established discrete foci of infection in the small intestine, eliciting the recruitment and transepithelial migration of neutrophils and inflammatory monocytes. Neutrophils accounted for a high proportion of actively invaded cells, and we provide evidence for a role for transmigrating neutrophils and other immune cells in the spread of T. gondii infection through the lumen of the intestine. Our data identify neutrophils as motile reservoirs of T. gondii infection and suggest a surprising retrograde pathway for parasite spread in the intestine.


Subject(s)
Cell Movement/immunology , Intestine, Small/immunology , Neutrophil Infiltration/immunology , Neutrophils/immunology , Toxoplasma/immunology , Toxoplasmosis/immunology , Animals , Disease Models, Animal , Immunity, Innate , Intestinal Mucosa/immunology , Intestinal Mucosa/parasitology , Intestinal Mucosa/pathology , Intestine, Small/parasitology , Intestine, Small/pathology , Mice , Mice, Transgenic , Microscopy, Confocal , Neutrophils/parasitology , Neutrophils/pathology , Toxoplasmosis/parasitology , Toxoplasmosis/pathology
11.
J Immunol ; 181(10): 7014-23, 2008 Nov 15.
Article in English | MEDLINE | ID: mdl-18981121

ABSTRACT

Little is known about the dynamics of the interactions between thymocytes and other cell types, as well as the spatiotemporal distribution of thymocytes during positive selection in the microenvironment of the cortex. We used two-photon laser scanning microscopy of the mouse thymus to visualize thymocytes and dendritic cells (DCs) and to characterize their interactions in the cortex. We show that thymocytes make frequent contacts with DCs in the thymic cortex and that these associations increase when thymocytes express T cell receptors that mediate positive selection. We also show that cortical DCs and the chemokine CCL21 expression are closely associated with capillaries throughout the cortex. The overexpression of the chemokine receptor CCR7 in thymocytes results in an increase in DC-thymocyte interactions, while the loss of CCR7 in the background of a positive-selecting TCR reduces the extent of DC-thymocyte interactions. These observations identify a vasculature-associated microenvironment within the thymic cortex that promotes interactions between DCs and thymocytes that are receiving positive selection signals.


Subject(s)
Cell Communication/immunology , Dendritic Cells/immunology , Receptors, CCR7/metabolism , T-Lymphocytes/immunology , Thymus Gland/cytology , Animals , Apoptosis/immunology , Capillaries/immunology , Cell Movement/immunology , Chemokine CCL21/metabolism , Dendritic Cells/cytology , Fluorescent Antibody Technique , Histocompatibility Antigens Class I , Image Processing, Computer-Assisted , In Situ Nick-End Labeling , Mice , Mice, Transgenic , Microscopy, Confocal , Receptors, Antigen, T-Cell/immunology , Self Tolerance/immunology , T-Lymphocytes/cytology , Thymus Gland/blood supply , Thymus Gland/immunology
12.
Immunity ; 29(3): 487-96, 2008 Sep 19.
Article in English | MEDLINE | ID: mdl-18718768

ABSTRACT

Although the signals that control neutrophil migration from the blood to sites of infection have been well characterized, little is known about their migration patterns within lymph nodes or the strategies that neutrophils use to find their local sites of action. To address these questions, we used two-photon scanning-laser microscopy to examine neutrophil migration in intact lymph nodes during infection with an intracellular parasite, Toxoplasma gondii. We found that neutrophils formed both small, transient and large, persistent swarms via a coordinated migration pattern. We provided evidence that cooperative action of neutrophils and parasite egress from host cells could trigger swarm formation. Neutrophil swarm formation coincided in space and time with the removal of macrophages that line the subcapsular sinus of the lymph node. Our data provide insights into the cellular mechanisms underlying neutrophil swarming and suggest new roles for neutrophils in shaping immune responses.


Subject(s)
Lymph Nodes/immunology , Macrophages/immunology , Neutrophils/immunology , Toxoplasma/immunology , Toxoplasmosis, Animal/immunology , Animals , Cell Movement , Lymph Nodes/cytology , Lymph Nodes/parasitology , Macrophages/cytology , Macrophages/parasitology , Mice , Neutrophils/cytology , Neutrophils/parasitology
13.
J Immunol ; 179(11): 7358-64, 2007 Dec 01.
Article in English | MEDLINE | ID: mdl-18025179

ABSTRACT

During thymic development, T cell progenitors undergo positive selection based on the ability of their T cell Ag receptors (TCR) to bind MHC ligands on thymic epithelial cells. Positive selection determines T cell fate, in that thymocytes whose TCR bind MHC class I (MHC-I) develop as CD8-lineage T cells, whereas those that bind MHC class II (MHC-II) develop as CD4 T cells. Positive selection also induces migration from the cortex to the medulla driven by the chemokine receptor CCR7. In this study, we show that CCR7 is up-regulated in a larger proportion of CD4(+)CD8(+) thymocytes undergoing positive selection on MHC-I compared with MHC-II. Mice bearing a mutation of Th-POK, a key CD4/CD8-lineage regulator, display increased expression of CCR7 among MHC-II-specific CD4(+)CD8(+) thymocytes. In addition, overexpression of CCR7 results in increased development of CD8 T cells bearing MHC-II-specific TCR. These findings suggest that the timing of CCR7 expression relative to coreceptor down-regulation is regulated by lineage commitment signals.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Lineage/immunology , Receptors, CCR7/biosynthesis , Thymus Gland/growth & development , Thymus Gland/immunology , Animals , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Cell Differentiation/immunology , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/immunology , Ligands , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Protein Binding , Receptors, Antigen, T-Cell/immunology , Receptors, CCR7/immunology , Thymus Gland/cytology , Transcription Factors/immunology , Up-Regulation/immunology
14.
J Immunol ; 174(2): 890-7, 2005 Jan 15.
Article in English | MEDLINE | ID: mdl-15634911

ABSTRACT

Both the Notch and TCR signaling pathways play an important role in T cell development, but the links between these signaling pathways are largely unexplored. The adapter protein Numb is a well-characterized inhibitor of Notch and also contains a phosphotyrosine binding domain, suggesting that Numb could provide a link between these pathways. We explored this possibility by investigating the physical interactions among Notch, Numb, and the TCR signaling apparatus and by examining the consequences of a Numb mutation on T cell development. We found that Notch and Numb cocluster with the TCR at the APC contact during Ag-driven T cell-APC interactions in both immature and mature T cells. Furthermore, Numb coimmunoprecipitates with components of the TCR signaling apparatus. Despite this association, T cell development and T cell activation occur normally in the absence of Numb, perhaps due to the expression of the related protein, Numblike. Together our data suggest that Notch and TCR signals may be integrated at the cell membrane, and that Numb may be an important adapter in this process.


Subject(s)
Membrane Proteins/physiology , Nerve Tissue Proteins/physiology , Receptors, Antigen, T-Cell/physiology , Receptors, Cell Surface/metabolism , Signal Transduction/immunology , T-Lymphocytes/metabolism , Transcription Factors/metabolism , Animals , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Cell Differentiation/genetics , Cell Differentiation/immunology , Cells, Cultured , Gene Deletion , Intracellular Signaling Peptides and Proteins , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mice , Mice, Transgenic , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Receptor, Notch1 , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Receptors, Cell Surface/physiology , Signal Transduction/genetics , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Thymus Gland/cytology , Thymus Gland/metabolism , Transcription Factors/physiology
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