CD8α+ and CD8α− Subclasses of Dendritic Cells Direct the Development of Distinct T Helper Cells In Vivo

Cells of the dendritic family display some unique properties that confer to them the capacity to sensitize naive T cells in vitro and in vivo. In the mouse, two subclasses of dendritic cells (DCs) have been described that differ by their CD8α expression and their localization in lymphoid organs. The physiologic function of both cell populations remains obscure. Studies conducted in vitro have suggested that CD8α+ DCs could play a role in the regulation of immune responses, whereas conventional CD8α− DCs would be more stimulatory. We report here that both subclasses of DCs efficiently prime antigen-specific T cells in vivo, and direct the development of distinct T helper (Th) populations. Antigen-pulsed CD8α+ and CD8α− DCs are separated after overnight culture in recombinant granulocyte/macrophage colony-stimulating factor and injected into the footpads of syngeneic mice. Administration of CD8α− DCs induces a Th2-type response, whereas injection of CD8α+ DCs leads to Th1 differentiation. We further show that interleukin 12 plays a critical role in Th1 development by CD8α+ DCs. These findings suggest that the nature of the DC that presents the antigen to naive T cells may dictate the class selection of the adaptative immune response.

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Effective Induction of Acquired Resistance to Listeria monocytogenes by Immunizing Mice with In Vivo-Infected Dendritic Cells

Infection and Immunity ◽

10.1128/iai.71.1.117-125.2003 ◽

2003 ◽

Vol 71 (1) ◽

pp. 117-125 ◽

Cited By ~ 15

Author(s):

Hiroshi Sashinami ◽

Akio Nakane ◽

Yoichiro Iwakura ◽

Mutsuo Sasaki

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Listeria Monocytogenes ◽

Critical Role ◽

Acquired Resistance ◽

Interleukin 12 ◽

Serovar Typhimurium ◽

Ifn Γ

ABSTRACT Splenic dendritic cells (DCs) obtained from mice at 48 h after Listeria monocytogenes infection exhibited up-regulation of CD80 and produced higher titers of gamma interferon (IFN-γ) and interleukin-12 (IL-12) than did DCs obtained from uninfected mice. Mice immunized with DCs obtained from mice that had been infected with L. monocytogenes 48 h before acquired host resistance to lethal infection with L. monocytogenes at 4 and 8 weeks. Immunization with DCs from heat-killed L. monocytogenes failed to induce resistance. Acquired antilisterial resistance is specific, since the immunized mice could not be protected from Salmonella enterica serovar Typhimurium infection. Infected DCs stimulated proliferation of naive CD4+ and CD8+ cells in vitro, suggesting that in vivo-infected DCs activate CD8+ T cells, which are critical in acquired antilisterial resistance, as well as CD4+ T cells. When wild-type mice were immunized with DCs from IFN-γ-deficient mice, they were protected against a lethal L. monocytogenes challenge. In contrast, when mice were immunized with DCs from anti-IL-12 p40 monoclonal antibody-injected mice, they failed to gain acquired antilisterial resistance. These results suggest that DC-derived IL-12, but not IFN-γ, may play a critical role in induction of acquired antilisterial resistance. Our present results suggest that splenic DCs obtained from mice infected with L. monocytogenes in vivo may be an effective immunogen with which to induce antigen-specific immunity.

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Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones.

Journal of Experimental Medicine ◽

10.1084/jem.179.4.1273 ◽

1994 ◽

Vol 179 (4) ◽

pp. 1273-1283 ◽

Cited By ~ 269

Author(s):

R Manetti ◽

F Gerosa ◽

M G Giudizi ◽

R Biagiotti ◽

P Parronchi ◽

...

Keyword(s):

T Cells ◽

Interferon Gamma ◽

Specific Antigen ◽

Th2 Cells ◽

Interleukin 12 ◽

T Helper ◽

Ifn Gamma ◽

Selection Of

Interleukin 12 (IL-12) facilitates the generation of a T helper type 1 (Th1) response, with high interferon gamma (IFN-gamma) production, while inhibiting the generation of IL-4-producing Th2 cells in polyclonal cultures of both human and murine T cells and in vivo in the mouse. In this study, we analyzed the effect of IL-12, present during cloning of human T cells, on the cytokine profile of the clones. The culture system used allows growth of clones from virtually every T cell, and thus excludes the possibility that selection of precommitted Th cell precursors plays a role in determining characteristics of the clones. IL-12 present during the cloning procedures endowed both CD4+ and CD8+ clones with the ability to produce IFN-gamma at levels severalfold higher than those observed in clones generated in the absence of IL-12. This priming was stable because the high levels of IFN-gamma production were maintained when the clones were cultured in the absence of IL-12 for 11 d. The CD4+ and some of the CD8+ clones produced variable amounts of IL-4. Unlike IFN-gamma, IL-4 production was not significantly different in clones generated in the presence or absence of IL-12. These data suggest that IL-12 primes the clone progenitors, inducing their differentiation to high IFN-gamma-producing clones. The suppression of IL-4-producing cells observed in polyclonally generated T cells in vivo and in vitro in the presence of IL-12 is not observed in this clonal model, suggesting that the suppression depends more on positive selection of non-IL-4-producing cells than on differentiation of individual clones. However, antigen-specific established Th2 clones that were unable to produce IFN-gamma with any other inducer did produce IFN-gamma at low but significant levels when stimulated with IL-12 in combination with specific antigen or insoluble anti-CD3 antibodies. This induction of IFN-gamma gene expression was transient, because culture of the established clones with IL-12 for up to 1 wk did not convert them into IFN-gamma producers when stimulated in the absence of IL-12. These results suggest that Th clones respond to IL-12 treatment either with a stable priming for IFN-gamma production or with only a transient low level expression of the IFN-gamma gene, depending on their stage of differentiation.

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

Journal of Experimental Medicine ◽

10.1084/jem.176.5.1431 ◽

1992 ◽

Vol 176 (5) ◽

pp. 1431-1437 ◽

Cited By ~ 156

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.

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WDFY4 is required for cross-presentation in response to viral and tumor antigens

Science ◽

10.1126/science.aat5030 ◽

2018 ◽

Vol 362 (6415) ◽

pp. 694-699 ◽

Cited By ~ 69

Author(s):

Derek J. Theisen ◽

Jesse T. Davidson ◽

Carlos G. Briseño ◽

Marco Gargaro ◽

Elvin J. Lauron ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Tumor Antigens ◽

Critical Role ◽

Tumor Rejection ◽

Interleukin 12 ◽

Cross Presentation ◽

Histocompatibility Complex ◽

Crispr Screen

During the process of cross-presentation, viral or tumor-derived antigens are presented to CD8+ T cells by Batf3-dependent CD8α+/XCR1+ classical dendritic cells (cDC1s). We designed a functional CRISPR screen for previously unknown regulators of cross-presentation, and identified the BEACH domain–containing protein WDFY4 as essential for cross-presentation of cell-associated antigens by cDC1s in mice. However, WDFY4 was not required for major histocompatibility complex class II presentation, nor for cross-presentation by monocyte-derived dendritic cells. In contrast to Batf3–/– mice, Wdfy4–/– mice displayed normal lymphoid and nonlymphoid cDC1 populations that produce interleukin-12 and protect against Toxoplasma gondii infection. However, similar to Batf3–/– mice, Wdfy4–/– mice failed to prime virus-specific CD8+ T cells in vivo or induce tumor rejection, revealing a critical role for cross-presentation in antiviral and antitumor immunity.

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Prostaglandin E2 Reverses the Effects of DNA Methyltransferase Inhibitor and TGFB1 on the Conversion of Naive T Cells to iTregs

Transfusion Medicine and Hemotherapy ◽

10.1159/000502582 ◽

2019 ◽

Vol 47 (3) ◽

pp. 244-253

Author(s):

Mehmet Sahin ◽

Emel Sahin

Keyword(s):

T Cells ◽

Prostaglandin E2 ◽

Dna Methyltransferase ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Naive T Cells ◽

Naïve T Cells ◽

Dna Methyltransferase Inhibitor

Naturally occurring regulatory T cells (nTregs) are produced under thymic (tTregs) or peripherally induced (pTregs) conditions in vivo. On the other hand, Tregs generated from naive T cells in vitro under some circumstances, such as treatment with transforming growth factor-β (TGFB), are called induced Tregs (iTregs). Tregs are especially characterized by FOXP3 expression, which is mainly controlled by DNA methylation. nTregs play important roles in the suppression of immune response and self-tolerance. The prostaglandin E2 (PGE2) pathway was reported to contribute to regulatory functions of tumor-infiltrating nTregs. In this study, we examined whether PGE2 contributes to the formation of iTregs treated with TGFB1 and 5-aza-2′-deoxycytidine (5-aza-dC), which is a DNA methyltransferase inhibitor. We found that the protein and gene expression levels of FOXP3 and IL-10 were increased in 5-aza-dC and TGFB1-treated T cells in vitro. However, the addition of PGE2 to these cells reversed these increments significantly. In CFSE-based cell suppression assays, we demonstrated that PGE2 decreased the suppressive functions of 5-aza-dC and TGFB1-treated T cells.

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Dendritic cells pulsed with Pythium insidiosum (1,3)(1,6)-β-glucan, Heat-inactivated zoospores and immunotherapy prime naïve T cells to Th1 differentiation in vitro

Immunobiology ◽

10.1016/j.imbio.2017.10.033 ◽

2018 ◽

Vol 223 (3) ◽

pp. 294-299 ◽

Cited By ~ 3

Author(s):

Pauline C. Ledur ◽

Juliana S.M. Tondolo ◽

Francielli P.K. Jesus ◽

Camila M. Verdi ◽

Érico S. Loreto ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Pythium Insidiosum ◽

Naive T Cells ◽

Naïve T Cells

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Steady-state dendritic cells expressing cognate antigen terminate memory CD8+ T-cell responses

Blood ◽

10.1182/blood-2007-07-103200 ◽

2008 ◽

Vol 111 (4) ◽

pp. 2091-2100 ◽

Cited By ~ 40

Author(s):

Tony J. Kenna ◽

Ranjeny Thomas ◽

Raymond J. Steptoe

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Steady State ◽

T Cell ◽

Developmental Plasticity ◽

Naive T Cells ◽

Naïve T Cells ◽

Cognate Antigen ◽

Costimulatory Signals

Antigen stimulation of naive T cells in conjunction with strong costimulatory signals elicits the generation of effector and memory populations. Such terminal differentiation transforms naive T cells capable of differentiating along several terminal pathways in response to pertinent environmental cues into cells that have lost developmental plasticity and exhibit heightened responsiveness. Because these cells exhibit little or no need for the strong costimulatory signals required for full activation of naive T cells, it is generally considered memory and effector T cells are released from the capacity to be inactivated. Here, we show that steady-state dendritic cells constitutively presenting an endogenously expressed antigen inactivate fully differentiated memory and effector CD8+ T cells in vivo through deletion and inactivation. These findings indicate that fully differentiated effector and memory T cells exhibit a previously unappreciated level of plasticity and provide insight into how memory and effector T-cell populations may be regulated.

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CD4+ CD25+ Regulatory T Cells Control T Helper Cell Type 1 Responses to Foreign Antigens Induced by Mature Dendritic Cells In Vivo

Journal of Experimental Medicine ◽

10.1084/jem.20030654 ◽

2003 ◽

Vol 198 (2) ◽

pp. 259-266 ◽

Cited By ~ 169

Author(s):

Guillaume Oldenhove ◽

Magali de Heusch ◽

Georgette Urbain-Vansanten ◽

Jacques Urbain ◽

Charlie Maliszewski ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Regulatory T Cells ◽

Immune Responses ◽

Peripheral Tolerance ◽

T Helper Cell ◽

Helper Cell ◽

T Helper

Recent evidence suggests that in addition to their well known stimulatory properties, dendritic cells (DCs) may play a major role in peripheral tolerance. It is still unclear whether a distinct subtype or activation status of DC exists that promotes the differentiation of suppressor rather than effector T cells from naive precursors. In this work, we tested whether the naturally occurring CD4+ CD25+ regulatory T cells (Treg) may control immune responses induced by DCs in vivo. We characterized the immune response induced by adoptive transfer of antigen-pulsed mature DCs into mice depleted or not of CD25+ cells. We found that the development of major histocompatibility complex class I and II–restricted interferon γ–producing cells was consistently enhanced in the absence of Treg. By contrast, T helper cell (Th)2 priming was down-regulated in the same conditions. This regulation was independent of interleukin 10 production by DCs. Of note, splenic DCs incubated in vitro with Toll-like receptor ligands (lipopolysaccharide or CpG) activated immune responses that remained sensitive to Treg function. Our data further show that mature DCs induced higher cytotoxic activity in CD25-depleted recipients as compared with untreated hosts. We conclude that Treg naturally exert a negative feedback mechanism on Th1-type responses induced by mature DCs in vivo.

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Murine Dendritic Cells Pulsed In Vitro withToxoplasma gondii Antigens Induce Protective Immunity In Vivo

Infection and Immunity ◽

10.1128/iai.66.10.4867-4874.1998 ◽

1998 ◽

Vol 66 (10) ◽

pp. 4867-4874 ◽

Cited By ~ 38

Author(s):

Isabelle Bourguin ◽

Muriel Moser ◽

Dominique Buzoni-Gatel ◽

Françoise Tielemans ◽

Daniel Bout ◽

...

Keyword(s):

Dendritic Cells ◽

Cellular Response ◽

Critical Role ◽

Cell Subset ◽

Surface Protein ◽

Interleukin 12 ◽

Pulsed Dc ◽

Microneme Protein

ABSTRACT The activation of a predominant T-helper-cell subset plays a critical role in disease resolution. In the case of Toxoplasma gondii, the available evidence indicates that CD4+protective cells belong to the Th1 subset. The aim of this study was to determine whether T. gondii antigens (in T. gondii sonicate [TSo]) presented by splenic dendritic cells (DC) were able to induce a specific immune response in vivo and to protect CBA/J mice orally challenged with T. gondiicysts. CBA/J mice immunized with TSo-pulsed DC exhibited significantly fewer cysts in their brains after oral infection with T. gondii 76K than control mice did. Protected mice developed a strong humoral response in vivo, with especially high levels of anti-TSo immunoglobulin G2a antibodies in serum. T. gondii antigens such as SAG1 (surface protein), SAG2 (surface protein), MIC1 (microneme protein), ROP2 through ROP4 (rhoptry proteins), and MIC2 (microneme protein) were recognized predominantly. Furthermore, DC loaded with TSo, which synthesized high levels of interleukin-12 (IL-12), triggered a strong cellular response in vivo, as assessed by the proliferation of lymph node cells in response to TSo restimulation in vitro. Cellular proliferation was associated with gamma interferon and IL-2 production. Taken together, these results indicate that immunization of CBA/J mice with TSo-pulsed DC can induce both humoral and Th1-like cellular immune responses and affords partial resistance against the establishment of chronic toxoplasmosis.

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