scholarly journals Microglia induce CD4 T lymphocyte final effector function and death.

1996 ◽  
Vol 184 (5) ◽  
pp. 1737-1745 ◽  
Author(s):  
A L Ford ◽  
E Foulcher ◽  
F A Lemckert ◽  
J D Sedgwick
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Tissue Macrophage ◽  
T Cell Survival

Microglia, a type of tissue macrophage, are the only cells in the central nervous system (CNS) parenchyma to express some major histocompatibility complex (MHC) class II constitutively or to upregulate expression readily. They are thought to play a role in CD4 T cell activation in autoimmune diseases such as multiple sclerosis, as well as in neurodegenerative conditions, Alzheimer's disease in particular. We show here that highly purified MHC class II+ microglia when tested directly ex vivo do indeed support an effector response by an encephalitogenic myelin basic protein-reactive CD4 T cell line from which production of the proinflammatory cytokines, interferon gamma and tumor necrosis factor, is elicited, but not interleukin (IL)-2 secretion or proliferation. After this interaction, the T cells die by apoptosis. Other nonmicroglial but CNS-associated macrophages isolated in parallel stimulate full T cell activation, including IL-2 production, proliferation, and support T cell survival. Neither CNS-derived population expresses B7.1/B7.2. Resident macrophages that terminate effector T cells in tissues constitute a novel and broadly applicable regulatory measure of particular relevance to processes of self-tolerance against sequestered antigens.

scholarly journals Identification of a CD4+ T cell-stimulating antigen of pathogenic bacteria by expression cloning.

1995 ◽  
Vol 182 (6) ◽  
pp. 1751-1757 ◽  
Author(s):  
S Sanderson ◽  
D J Campbell ◽  
N Shastri
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Pathogenic Bacteria ◽  
Genomic Library ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Expression Cloning

Identifying the immunogenic proteins that elicit pathogen-specific T cell responses is key to rational vaccine design. While several approaches have succeeded in identifying major histocompatibility complex (MHC) class I bound peptides that stimulate CD8+ T cells, these approaches have been difficult to extend to peptides presented by MHC class II molecules that stimulate CD4+ T cells. We describe here a novel strategy for identifying CD4+ T cell-stimulating antigen genes. Using Listeria monocytogenes-specific, lacZ-inducible T cells as single-cell probes, we screened a Listeria monocytogenes genomic library as recombinant Escherichia coli that were fed to macrophages. The antigen gene was isolated from the E. coli clone that, when ingested by the macrophages, allowed generation of the appropriate peptide/MHC class II complex and T cell activation. We show that the antigenic peptide is derived from a previously unknown listeria gene product with characteristics of a membrane-bound protein.

scholarly journals H2-M and H2-O as Targeting Vehicles for the MHC Class II Processing Compartment Promote Antigen-Specific CD4+ T Cell Activation

Vaccines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1053
Author(s):  
Lucia Lapazio ◽  
Monika Braun ◽  
Kaj Grandien
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Antigen Presentation Pathway ◽  
Presentation Pathway ◽  
Class Ii Antigen ◽  
Mhc Class Ii Antigen

CD8 and CD4 T cell activation are both required for a strong and long-lasting T cell immune response. Endogenously expressed proteins are readily processed by the MHC class I antigen presentation pathway, enabling activation of CD8+ T cells. However, the MHC class II antigen presentation pathway, necessary for CD4+ T cell activation, is generally not sufficiently accessible to endogenously expressed proteins, limiting the efficiency of mRNA- or DNA-based vaccines. In the current study, we have evaluated the feasibility of using antigen sequences fused to sequences derived from the H2-M and H2-O proteins, two complexes known to participate in MHC class II antigen processing, for the enhancement of CD4 T-cell activation. We analyzed T cell activation after genetic immunization with mRNA-encoding fusion proteins with the model antigen ovalbumin and sequences derived from H2-M or H2-O. Our results show that H2-M- or H2-O-derived sequences robustly improve antigen-specific CD4 T-cell activation when fused to the antigen of interest and suggest that the approach could be used to improve the efficiency of mRNA- or DNA-based vaccines.

scholarly journals Selective immunosuppression by administration of major histocompatibility complex (MHC) class II-binding peptides. I. Evidence for in vivo MHC blockade preventing T cell activation.

1992 ◽  
Vol 175 (5) ◽  
pp. 1345-1352 ◽  
Author(s):  
J C Guéry ◽  
A Sette ◽  
J Leighton ◽  
A Dragomir ◽  
L Adorini
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
Specific Class ◽  
Binding Peptide

Draining lymph node cells (LNC) from mice immunized with hen egg white lysozyme (HEL) display at their surface antigen-MHC complexes able to stimulate, in the absence of any further antigen addition, HEL peptide-specific, class II-restricted T cell hybridomas. Chloroquine addition to these LNC cultures fails to inhibit antigen presentation, indicating that antigenic complexes of class II molecules and HEL peptides are formed in vivo. MHC class II restriction of antigen presentation by LNC from HEL-primed mice was verified by the use of anti-class II monoclonal antibodies. Coinjection of HEL and the I-Ak-binding peptide HEL 112-129 in mice of H-2k haplotype inhibits the ability of LNC to stimulate I-Ak-restricted, HEL 46-61-specific T cell hybridomas. Similar results are obtained in mice coinjected with the HEL peptides 46-61 and 112-129. Inhibition of T hybridoma activation can also be observed using as antigen-presenting cells irradiated, T cell-depleted LNC from mice coinjected with HEL 46-61 and HEL 112-129, ruling out the possible role of either specific or nonspecific suppressor T cells. Inhibition of T cell proliferation is associated with MHC-specific inhibition of antigen presentation and with occupancy by the competitor of class II binding sites, as measured by activation of peptide-specific T cell hybridomas. These results demonstrate that administration of MHC class II binding peptide competitors selectively inhibits antigen presentation to class II-restricted T cells, indicating competitive blockade of class II molecules in vivo.

CD4+ T-cell activation for immunotherapy of malignancies using Ii-Key/MHC class II epitope hybrid vaccines

Vaccine ◽  
2012 ◽  
Vol 30 (18) ◽  
pp. 2805-2810 ◽  
Author(s):  
Minzhen Xu ◽  
Nikoletta L. Kallinteris ◽  
Eric von Hofe
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
Cd4 T Cell

scholarly journals Deciphering the Plasmodium falciparum malaria-specific CD4+ T cell response: ex vivo detection of high frequencies of PD-1+TIGIT+ EXP1-specific CD4+ T cells using a novel HLA-DR11-restricted MHC class II tetramer

2021 ◽  
Author(s):  
Sophia Schulte ◽  
Janna Heide ◽  
Christin Ackermann ◽  
Sven Peine ◽  
Michael Ramharter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cell Response ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Class Ii ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Inhibitory Receptors

Abstract Relatively little is known about the ex vivo frequency and phenotype of the P. falciparum-specific CD4+ T cell response in humans. The exported protein 1 (EXP1) is expressed by plasmodia at both, the liver stage and blood stage, of infection making it a potential target for CD4+ and CD8+ effector T cells. Here, a fluorochrome-labelled HLA-DRB1*11:01-restriced MHC class II tetramer derived from the P. falciparum EXP1 (aa62-74) was established for ex vivo tetramer analysis and magnetic bead enrichment in ten patients with acute malaria. EXP1-specific CD4+ T cells were detectable in nine out of ten (90%) malaria patients expressing the HLA-DRB1*11 molecule with an average ex vivo frequency of 0.11% (0-0.22%) of total CD4+ T cells. The phenotype of EXP1-specific CD4+ T cells was further assessed using co-staining with activation (CD38, HLA-DR, CD26), differentiation (CD45RO, CCR7, KLRG1, CD127), senescence (CD57) and co-inhibitory (PD-1, TIGIT, LAG-3, TIM-3) markers as well as the ectonucleotidases CD39 and CD73. EXP1-specific tetramer+ CD4+ T cells had a distinct phenotype compared to bulk CD4+ T cells and displayed a highly activated effector memory phenotype with elevated levels of co-inhibitory receptors and activation markers: EXP1-specific CD4+ T cells universally expressed the co-inhibitory receptors PD-1 and TIGIT as well as the activation marker CD38 and showed elevated frequencies of CD39. These results demonstrate that MHC class II tetramer enrichment is a sensitive approach to investigate ex vivo antigen-specific CD4+ T cells in malaria patients that will aid further analysis of the role of CD4+ T cells during malaria.

CD4 function in thymocyte differentiation and T cell activation

1993 ◽  
Vol 342 (1299) ◽  
pp. 25-34 ◽  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Subset ◽  
Class Ii ◽  
Class I ◽  
Double Positive

The ectodomains of the T cell surface glycoproteins CD4 and CD8 bind to membrane-proximal domains of MHC class II and class I molecules, respectively, while both cytoplasmic domains interact with the protein tyrosine kinase (PTK) p56 lck (lck) through a shared cysteine-containing motif. Function of CD4 and CD8 requires their binding to the same MHC molecule as that recognized by the T cell antigen receptor (TCR). In vitro studies indicate that CD4-associated lck functions even in the absence of kinase activity. In vivo experiments show that, whereas helper T cell development is impaired in CD4-deficient mice, high level expression of a transgenic CD4 that cannot bind lck rescues development of this T cell subset. These studies suggest that CD4 is an adhesion molecule whose localization is regulated through protein-protein interactions of the associated PTK and whose function is to increase the stability of the TCR signalling complex by binding to the relevant MHC. The function of CD4 in development has been further studied in the context of how double positive (CD4+ CD8+ ) thymocytes mature into either CD4 + T cells with helper function and TCR specificity for class II or into CD8 + T cells with cytotoxic function and specificity for class I. Studies using CD4- transgenic mice indicate that development of single positive T cells involves stochastic downregulation of either CD4 or CD8, coupled to activation of a cytotoxic or helper program, respectively, and subsequent selection based on the ability of the TCR and remaining coreceptor to engage the same MHC molecule.

scholarly journals CD4 T-Cell Suppression by Cells from Toxoplasma gondii-Infected Retinas Is Mediated by Surface Protein PD-L1

2010 ◽  
Vol 78 (8) ◽  
pp. 3484-3492 ◽  
Author(s):  
Elizabeth Charles ◽  
Sunil Joshi ◽  
John D. Ash ◽  
Barbara A. Fox ◽  
A. Darise Farris ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Flow Cytometric Analysis ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Dependent Manner ◽  
Retinal Cells

ABSTRACT In the inflamed retina, CD4+ T cells can cause retinal damage when they are not properly regulated. Since tissue expression of major histocompatibility complex (MHC) class II and costimulatory molecules is a key mechanism for regulating effector T cells, we tested the hypothesis that upregulation of these proteins in the retina contributes to the regulation of CD4 T cells. Here we report that in retinas infected with the protozoan parasite Toxoplasma gondii, MHC class II is upregulated on infiltrating leukocytes as well as on resident retinal cells, including photoreceptors. Flow cytometric analysis indicated that B7 costimulatory family members (CD80, CD86, ICOS-L, and programmed death ligand 2 [PD-L2]) were not expressed on class II+ cells. In contrast, PD-L1 (also named B7-H1 or CD274) was expressed on the majority of both hematopoietic and resident retinal MHC class II-expressing cells. Retinal cells from Toxoplasma-infected animals were able to suppress T-cell activation in a PD-L1-dependent manner. Finally, we demonstrate that the expression of MHC class II and PD-L1 was critically dependent on gamma interferon (IFN-γ) expression. These data suggest that retinal MHC class II and PD-L1 expression is a novel mechanism by which the retina protects itself from CD4 T-cell-mediated immune damage in ocular toxoplasmosis and other types of retinal immune responses.

scholarly journals Potent T Cell Activation with Dimeric Peptide–Major Histocompatibility Complex Class II Ligand: The Role of CD4 Coreceptor

1998 ◽  
Vol 188 (9) ◽  
pp. 1633-1640 ◽  
Author(s):  
Abdel Rahim A. Hamad ◽  
Sean M. O'Herrin ◽  
Michael S. Lebowitz ◽  
Ananth Srikrishnan ◽  
Joan Bieler ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

The interaction of the T cell receptor (TCR) with its cognate peptide–major histocompatibility complex (MHC) on the surface of antigen presenting cells (APCs) is a primary event during T cell activation. Here we used a dimeric IEk-MCC molecule to study its capacity to activate antigen-specific T cells and to directly analyze the role of CD4 in physically stabilizing the TCR–MHC interaction. Dimeric IEk-MCC stably binds to specific T cells. In addition, immobilized dimeric IEk-MCC can induce TCR downregulation and activate antigen-specific T cells more efficiently than anti-CD3. The potency of the dimeric IEk-MCC is significantly enhanced in the presence of CD4. However, CD4 does not play any significant role in stabilizing peptide-MHC–TCR interactions as it fails to enhance binding of IEk-MCC to specific T cells or influence peptide-MHC–TCR dissociation rate or TCR downregulation. Moreover, these results indicate that dimerization of peptide-MHC class II using an IgG molecular scaffold significantly increases its binding avidity leading to an enhancement of its stimulatory capacity while maintaining the physiological properties of cognate peptide–MHC complex. These peptide-MHC–IgG chimeras may, therefore, provide a novel approach to modulate antigen-specific T cell responses both in vitro and in vivo.

scholarly journals Inhibition of T Cells Provides Protection against Early Invasive Pneumococcal Disease

2010 ◽  
Vol 78 (12) ◽  
pp. 5287-5294 ◽  
Author(s):  
Kim LeMessurier ◽  
Hans Häcker ◽  
Elaine Tuomanen ◽  
Vanessa Redecke
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Invasive Pneumococcal Disease ◽  
T Cell Activation ◽  
Pneumococcal Disease ◽  
Cell Activation ◽  
Class Ii ◽  
Invasive Infection ◽  
Deficient Mice

ABSTRACT Infections caused by Streptococcus pneumoniae are major causes of morbidity and mortality, which are in part mediated by immune cell-dependent mechanisms. Yet, the specific contributions of individual cell types to immunopathology are only partially understood. T cells are well characterized with respect to their function in protective humoral immune responses; however, their roles during early stages of infection and invasive pneumococcal disease (IPD) are less well defined. Using a mouse model of pneumococcal sepsis, we found that CD4+ T cells were recruited to the lung as early as 12 h after intranasal infection. Recruitment was accompanied by upregulation of CD69 and B7-H1, reflecting T-cell activation. Unexpectedly, major histocompatibility complex (MHC) class II-deficient mice, which lack CD4+ T cells, displayed an increased survival despite comparable bacterial titers in the blood, spleen, and lung. The higher survival correlated with a lower cytokine and chemokine response upon S. pneumoniae challenge in MHC class II-deficient mice, suggesting that inflammation may contribute to the mortality of IPD. Comparable to the case for MHC class II-deficient mice, antibody-mediated depletion of CD4+ T cells and drug-induced inhibition of T-cell function with cyclosporine, or interference with T-cell activation using CTLA4-immunoglobulin (Abatacept), led to significant increases in survival during IPD. Our results reveal an important and adverse role of CD4+ T cells in the pathogenesis of IPD and suggest that modulation of T-cell activation during early phases of S. pneumoniae invasive infection may provide a therapeutic option.

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