scholarly journals MHC Class II Expression Restricted to CD8α+ and CD11b+ Dendritic Cells Is Sufficient for Control of Leishmania major

2004 ◽  
Vol 199 (5) ◽  
pp. 725-730 ◽  
Author(s):  
Maria P. Lemos ◽  
Fatima Esquivel ◽  
Phillip Scott ◽  
Terri M. Laufer
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Cd4 T Cell ◽  
Major Infection ◽  
Mhc Ii ◽  
Antigen Presenting

Control of the intracellular protozoan, Leishmania major, requires major histocompatibility complex class II (MHC II)–dependent antigen presentation and CD4+ T cell T helper cell 1 (Th1) differentiation. MHC II–positive macrophages are a primary target of infection and a crucial effector cell controlling parasite growth, yet their function as antigen-presenting cells remains controversial. Similarly, infected Langerhans cells (LCs) can prime interferon (IFN)γ–producing Th1 CD4+ T cells, but whether they are required for Th1 responses is unknown. We explored the antigen-presenting cell requirement during primary L. major infection using a mouse model in which MHC II, I-Aβb, expression is restricted to CD11b+ and CD8α+ dendritic cells (DCs). Importantly, B cells, macrophages, and LCs are all MHC II–negative in these mice. We demonstrate that antigen presentation by these DC subsets is sufficient to control a subcutaneous L. major infection. CD4+ T cells undergo complete Th1 differentiation with parasite-specific secretion of IFNγ. Macrophages produce inducible nitric oxide synthase, accumulate at infected sites, and control parasite numbers in the absence of MHC II expression. Therefore, CD11b+ and CD8α+ DCs are not only key initiators of the primary response but also provide all the necessary cognate interactions for CD4+ T cell Th1 effectors to control this protozoan infection.

scholarly journals Second Class Minors

2003 ◽  
Vol 197 (3) ◽  
pp. 375-385 ◽  
Author(s):  
Hiroeki Sahara ◽  
Nilabh Shastri
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Interleukin 4 ◽  
General Strategy ◽  
Mhc Ii ◽  
Cell Responses ◽  
Antigen Presenting

CD4 T cells regulate immune responses that cause chronic graft rejection and graft versus host disease but their target antigens remain virtually unknown. We developed a new method to identify CD4 T cell–stimulating antigens. LacZ-inducible CD4 T cells were used as a probe to detect their cognate peptide/MHC II ligand generated in dendritic cells fed with Escherichia coli expressing a library of target cell genes. The murine H46 locus on chromosome 7 was thus found to encode the interleukin 4–induced IL4i1 gene. The IL4i1 precursor contains the HAFVEAIPELQGHV peptide which is presented by Ab major histocompatibility complex class II molecule via an endogenous pathway in professional antigen presenting cells. Both allelic peptides bind Ab and a single alanine to methionine substitution at p2 defines nonself. These results reveal novel features of H loci that regulate CD4 T cell responses as well as provide a general strategy for identifying elusive antigens that elicit CD4 T cell responses to tumors or self-tissues in autoimmunity.

scholarly journals CD4+ T Cell Polarization in Mice Is Modulated by Strain-specific Major Histocompatibility Complex–independent Differences within Dendritic Cells

2003 ◽  
Vol 198 (2) ◽  
pp. 201-209 ◽  
Author(s):  
Christophe Filippi ◽  
Stéphanie Hugues ◽  
Julie Cazareth ◽  
Valérie Julia ◽  
Nicolas Glaichenhaus ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Inbred Mice ◽  
Cell Polarization ◽  
Cd4 T Cell ◽  
Effector Cells ◽  
Th1 And Th2 Responses

Resistance and susceptibility to Leishmania major in mice are determined by multiple genes and correlate with the preferential development of Th1 and Th2 responses, respectively. Here, we found that CD11b+ dendritic cells (DCs) prime parasite-specific CD4+ T cells in both susceptible BALB/c (H2-d) and resistant B10.D2 (H2-d) mice. However, BALB/c and B10.D2 DCs from L. major–infected mice differ in their ability to polarize naive T cells into Th1 or Th2 effector cells. This difference is cell-intrinsic, is not restricted to H2-d mice, and is observed with both parasite-specific and allospecific CD4+ T cells. Thus, strain-specific differences within CD11b+ DCs influence the ability of inbred mice to mount polarized CD4+ T cell responses.

scholarly journals Response of naive antigen-specific CD4+ T cells in vitro: characteristics and antigen-presenting cell requirements.

1992 ◽  
Vol 176 (5) ◽  
pp. 1431-1437 ◽  
Author(s):  
M Croft ◽  
D D Duncan ◽  
S L Swain
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 Cells ◽  
Peptide Antigen ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Antigen Presenting

Because of the low frequency of T cells for any particular soluble protein antigen in unprimed animals, the requirements for naive T cell responses in specific antigens have not been clearly delineated and they have been difficult to study in vitro. We have taken advantage of mice transgenic for the V beta 3/V alpha 11 T cell receptor (TCR), which can recognize a peptide of cytochrome c presented by IEk. 85-90% of CD4+ T cells in these mice express the transgenic TCR, and we show that almost all such V beta 3/V alpha 11 receptor-positive cells have a phenotype characteristic of naive T cells, including expression of high levels of CD45RB, high levels of L-selectin (Mel-14), low levels of CD44 (Pgp-1), and secretion of interleukin 2 (IL-2) as the major cytokine. Naive T cells, separated on the basis of CD45RB high expression, gave vigorous responses (proliferation and IL-2 secretion) to peptide antigen presented in vitro by a mixed antigen-presenting cell population. At least 50% of the T cell population appeared to respond, as assessed by blast transformation, entry into G1, and expression of increased levels of CD44 by 24 h. Significant contributions to the response by contaminating memory CD4+ cells were ruled out by demonstrating that the majority of the CD45RB low, L-selectin low, CD44 high cells did not express the V beta 3/V alpha 11 TCR and responded poorly to antigen. We find that proliferation and IL-2 secretion of the naive CD4 cells is minimal when resting B cells present peptide antigen, and that both splenic and bone marrow-derived macrophages are weak stimulators. Naive T cells did respond well to high numbers of activated B cells. However, dendritic cells were the most potent stimulators of proliferation and IL-2 secretion at low cell numbers, and were far superior inducers of IL-2 at higher numbers. These studies establish that naive CD4 T cells can respond vigorously to soluble antigen and indicate that maximal stimulation can be achieved by presentation of antigen on dendritic cells. This model should prove very useful in further investigations of activation requirements and functional characteristics of naive helper T cells.

scholarly journals Isolevuglandin-Modified Cardiac Proteins Drive CD4+ T Cell Activation in the Heart and Promote Cardiac Dysfunction

Circulation ◽  
2021 ◽  
Author(s):  
Njabulo Ngwenyama ◽  
Annet Kirabo ◽  
Mark Aronovitz ◽  
Francisco Velázquez ◽  
Francisco Carrillo-Salinas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cardiac Dysfunction ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Myocardial Oxidative Stress

Background: Despite the well-established association between T cell-mediated inflammation and non-ischemic heart failure (HF), the specific mechanisms triggering T cell activation during the progression of HF and the antigens involved are poorly understood. We hypothesized that myocardial oxidative stress induces the formation of isolevuglandin (IsoLG)-modified proteins that function as cardiac neoantigens to elicit CD4+ T cell receptor (TCR) activation and promote HF. Methods: We used transverse aortic constriction (TAC) in mice to trigger myocardial oxidative stress and T cell infiltration. We profiled the TCR repertoire by mRNA sequencing of intramyocardial activated CD4+ T cells in Nur77 GFP reporter mice, which transiently express GFP upon TCR engagement. We assessed the role of antigen presentation and TCR specificity in the development of cardiac dysfunction using antigen presentation-deficient MhcII -/- mice, and TCR transgenic OTII mice that lack specificity for endogenous antigens. We detected IsoLG-protein adducts in failing human hearts. We also evaluated the role of reactive oxygen species (ROS) and IsoLGs in eliciting T cell immune responses in vivo by treating mice with the antioxidant TEMPOL, and the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) during TAC, and ex-vivo in mechanistic studies of CD4+ T cell proliferation in response to IsoLG-modified cardiac proteins. Results: We discovered that TCR antigen recognition increases in the left ventricle (LV) as cardiac dysfunction progresses, and identified a limited repertoire of activated CD4+ T cell clonotypes in the LV. Antigen presentation of endogenous antigens was required to develop cardiac dysfunction since MhcII -/- mice reconstituted with CD4+ T cells, and OTII mice immunized with their cognate antigen were protected from TAC-induced cardiac dysfunction despite the presence of LV-infiltrated CD4+ T cells. Scavenging IsoLGs with 2-HOBA reduced TCR activation and prevented cardiac dysfunction. Mechanistically, cardiac pressure overload resulted in ROS dependent dendritic cell accumulation of IsoLG-protein adducts which induced robust CD4+ T cell proliferation. Conclusions: Collectively, our study demonstrates an important role of ROS-induced formation of IsoLG-modified cardiac neoantigens that lead to TCR-dependent CD4+ T cell activation within the heart.

scholarly journals Contact-dependent delivery of IL-2 by dendritic cells to CD4 T cells in the contraction phase promotes their long-term survival

2019 ◽  
Vol 11 (2) ◽  
pp. 108-123
Author(s):  
Dan Tong ◽  
Li Zhang ◽  
Fei Ning ◽  
Ying Xu ◽  
Xiaoyu Hu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Immune Memory ◽  
Term Survival

Abstract Common γ chain cytokines are important for immune memory formation. Among them, the role of IL-2 remains to be fully explored. It has been suggested that this cytokine is critically needed in the late phase of primary CD4 T cell activation. Lack of IL-2 at this stage sets for a diminished recall response in subsequent challenges. However, as IL-2 peak production is over at this point, the source and the exact mechanism that promotes its production remain elusive. We report here that resting, previously antigen-stimulated CD4 T cells maintain a minimalist response to dendritic cells after their peak activation in vitro. This subtle activation event may be induced by DCs without overt presence of antigen and appears to be stronger if IL-2 comes from the same dendritic cells. This encounter reactivates a miniature IL-2 production and leads a gene expression profile change in these previously activated CD4 T cells. The CD4 T cells so experienced show enhanced reactivation intensity upon secondary challenges later on. Although mostly relying on in vitro evidence, our work may implicate a subtle programing for CD4 T cell survival after primary activation in vivo.

scholarly journals CD4+ T-cell killing of multiple myeloma cells is mediated by resident bone marrow macrophages

2020 ◽  
Vol 4 (12) ◽  
pp. 2595-2605 ◽  
Author(s):  
Ole Audun W. Haabeth ◽  
Kjartan Hennig ◽  
Marte Fauskanger ◽  
Geir Åge Løset ◽  
Bjarne Bogen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
Bone Marrow Microenvironment ◽  
Cd4 T Cell ◽  
Myeloma Cells ◽  
Antigen Presenting

Abstract CD4+ T cells may induce potent antitumor immune responses through interaction with antigen-presenting cells within the tumor microenvironment. Using a murine model of multiple myeloma, we demonstrated that adoptive transfer of idiotype-specific CD4+ T cells may elicit curative responses against established multifocal myeloma in bone marrow. This finding indicates that the myeloma bone marrow niche contains antigen-presenting cells that may be rendered tumoricidal. Given the complexity of the bone marrow microenvironment, the mechanistic basis of such immunotherapeutic responses is not known. Through a functional characterization of antitumor CD4+ T-cell responses within the bone marrow microenvironment, we found that killing of myeloma cells is orchestrated by a population of bone marrow–resident CD11b+F4/80+MHC-IIHigh macrophages that have taken up and present secreted myeloma protein. The present results demonstrate the potential of resident macrophages as powerful mediators of tumor killing within the bone marrow and provide a basis for novel therapeutic strategies against multiple myeloma and other malignancies that affect the bone marrow.

scholarly journals Telomerase and CD4 T Cell Immunity in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1687
Author(s):  
Magalie Dosset ◽  
Andrea Castro ◽  
Hannah Carter ◽  
Maurizio Zanetti
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Tumor Formation ◽  
T Cell Immunity ◽  
Cd4 T Cell ◽  
Current Status ◽  
Mhc Ii ◽  
Cell Immunity

Telomerase reverse transcriptase (TERT) is a conserved self-tumor antigen which is overexpressed in most tumors and plays a critical role in tumor formation and progression. As such, TERT is an antigen of great relevance to develop widely applicable immunotherapies. CD4 T cells play a major role in the anti-cancer response alone or with other effector cells such as CD8 T cells and NK cells. To date, efforts have been made to identify TERT peptides capable of stimulating CD4 T cells that are also able to bind diverse MHC-II alleles to ease immune status monitoring and immunotherapies. Here, we review the current status of TERT biology, TERT/MHC-II immunobiology, and past and current vaccine clinical trials. We propose that monitoring CD4 T cell immunity against TERT is a simple and direct way to assess immune surveillance in cancer patients and a new way to predict the response to immune checkpoint inhibitors (ICPi). Finally, we present the initial results of a systematic discovery of TERT peptides able to bind the most common HLA Class II alleles worldwide and show that the repertoire of MHC-II TERT peptides is wider than currently appreciated.

scholarly journals The critical role of CD4+ T cells in PD-1 blockade against MHC-II–expressing tumors such as classic Hodgkin lymphoma

2020 ◽  
Vol 4 (17) ◽  
pp. 4069-4082
Author(s):  
Joji Nagasaki ◽  
Yosuke Togashi ◽  
Takeaki Sugawara ◽  
Makiko Itami ◽  
Nobuhiko Yamauchi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Cd4 T Cell ◽  
Antitumor Effects ◽  
Cell Axis ◽  
Mhc I ◽  
Mhc Ii

Abstract Classic Hodgkin lymphoma (cHL) responds markedly to PD-1 blockade therapy, and the clinical responses are reportedly dependent on expression of major histocompatibility complex class II (MHC-II). This dependence is different from other solid tumors, in which the MHC class I (MHC-I)/CD8+ T-cell axis plays a critical role. In this study, we investigated the role of the MHC-II/CD4+ T-cell axis in the antitumor effect of PD-1 blockade on cHL. In cHL, MHC-I expression was frequently lost, but MHC-II expression was maintained. CD4+ T cells highly infiltrated the tumor microenvironment of MHC-II–expressing cHL, regardless of MHC-I expression status. Consequently, CD4+ T-cell, but not CD8+ T-cell, infiltration was a good prognostic factor in cHL, and PD-1 blockade showed antitumor efficacy against MHC-II–expressing cHL associated with CD4+ T-cell infiltration. Murine lymphoma and solid tumor models revealed the critical role of antitumor effects mediated by CD4+ T cells: an anti-PD-1 monoclonal antibody exerted antitumor effects on MHC-I−MHC-II+ tumors but not on MHC-I−MHC-II− tumors, in a cytotoxic CD4+ T-cell–dependent manner. Furthermore, LAG-3, which reportedly binds to MHC-II, was highly expressed by tumor-infiltrating CD4+ T cells in MHC-II–expressing tumors. Therefore, the combination of LAG-3 blockade with PD-1 blockade showed a far stronger antitumor immunity compared with either treatment alone. We propose that PD-1 blockade therapies have antitumor effects on MHC-II–expressing tumors such as cHL that are mediated by cytotoxic CD4+ T cells and that LAG-3 could be a candidate for combination therapy with PD-1 blockade.

scholarly journals Enteral Immunization with Attenuated Recombinant Listeria monocytogenes as a Live Vaccine Vector: Organ-Dependent Dynamics of CD4 T Lymphocytes Reactive to a Leishmania major Tracer Epitope

2003 ◽  
Vol 71 (3) ◽  
pp. 1083-1090 ◽  
Author(s):  
Hélène Saklani-Jusforgues ◽  
Elisabeth Fontan ◽  
Neirouz Soussi ◽  
Geneviève Milon ◽  
Pierre L. Goossens
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
T Cell ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Cd4 T Cell ◽  
Interleukin 4 ◽  
Cell Immune Response ◽  
Mesenteric Lymph Nodes ◽  
Ifn Γ

ABSTRACT Listeria monocytogenes is considered as a potential live bacterial vector, particularly for the induction of CD8 T cells. The CD4 T-cell immune response triggered after enteral immunization of mice has not yet been thoroughly characterized. The dynamics of gamma interferon (IFN-γ)- and interleukin-4 (IL-4)-secreting CD4 T cells were analyzed after priming through intragastric delivery of an attenuated ΔactA recombinant L. monocytogenes strain expressing the Leishmania major LACK protein; a peptide of this protein, LACK158-173 peptide (pLACK), is a well-characterized CD4 T-cell target in BALB/c mice. Five compartments were monitored: Peyer's patches, mesenteric lymph nodes (MLN), spleen, liver, and blood. A single intragastric inoculation of ΔactA-LACK-LM in BALB/c mice led to colonization of the MLN and spleen at a significant level for at least 3 days. Efficient priming of IFN-γ-secreting pLACK-reactive CD4 T cells was observed in all tested compartments. Interestingly, IL-4-secreting pLACK-reactive CD4 T cells were detectable at day 6 or 7 only in blood and liver. The absence of translocation of viable bacteria through the intestinal epithelium after further ΔactA-LACK-LM inoculations was concomitant with the absence of an increase in the level of IFN-γ secreted by the MLN, blood, and splenic pLACK-reactive Th1 T cells, although the levels remained significantly above the basal level. No change in this population size was detected in the spleen. However, an increase in the number of intragastric inoculations had a clinical beneficial effect in L. major-infected BALB/c mice. L. monocytogenes thus presents the potential of an efficient vector for induction of CD4 T cells when administered by the enteral route.

scholarly journals Direct Expansion of Functional CD25+ CD4+ Regulatory T Cells by Antigen-processing Dendritic Cells

2003 ◽  
Vol 198 (2) ◽  
pp. 235-247 ◽  
Author(s):  
Sayuri Yamazaki ◽  
Tomonori Iyoda ◽  
Kristin Tarbell ◽  
Kara Olson ◽  
Klara Velinzon ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Antigen Processing ◽  
Specific Antigen ◽  
Cell Receptor ◽  
Cd4 T Cell

An important pathway for immune tolerance is provided by thymic-derived CD25+ CD4+ T cells that suppress other CD25− autoimmune disease–inducing T cells. The antigen-presenting cell (APC) requirements for the control of CD25+ CD4+ suppressor T cells remain to be identified, hampering their study in experimental and clinical situations. CD25+ CD4+ T cells are classically anergic, unable to proliferate in response to mitogenic antibodies to the T cell receptor complex. We now find that CD25+ CD4+ T cells can proliferate in the absence of added cytokines in culture and in vivo when stimulated by antigen-loaded dendritic cells (DCs), especially mature DCs. With high doses of DCs in culture, CD25+ CD4+ and CD25− CD4+ populations initially proliferate to a comparable extent. With current methods, one third of the antigen-reactive T cell receptor transgenic T cells enter into cycle for an average of three divisions in 3 d. The expansion of CD25+ CD4+ T cells stops by day 5, in the absence or presence of exogenous interleukin (IL)-2, whereas CD25− CD4+ T cells continue to grow. CD25+ CD4+ T cell growth requires DC–T cell contact and is partially dependent upon the production of small amounts of IL-2 by the T cells and B7 costimulation by the DCs. After antigen-specific expansion, the CD25+ CD4+ T cells retain their known surface features and actively suppress CD25− CD4+ T cell proliferation to splenic APCs. DCs also can expand CD25+ CD4+ T cells in the absence of specific antigen but in the presence of exogenous IL-2. In vivo, both steady state and mature antigen-processing DCs induce proliferation of adoptively transferred CD25+ CD4+ T cells. The capacity to expand CD25+ CD4+ T cells provides DCs with an additional mechanism to regulate autoimmunity and other immune responses.

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