scholarly journals Critical Contribution of Ox40 Ligand to T Helper Cell Type 2 Differentiation in Experimental Leishmaniasis

2000 ◽  
Vol 191 (2) ◽  
pp. 375-380 ◽  
Author(s):  
Hisaya Akiba ◽  
Yasushi Miyahira ◽  
Machiko Atsuta ◽  
Kazuyoshi Takeda ◽  
Chiyoko Nohara ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Critical Role ◽  
Flow Cytometric Analysis ◽  
Th2 Cells ◽  
Mouse Strains ◽  
T Helper

Infection of inbred mouse strains with Leishmania major is a well characterized model for analysis of T helper (Th)1 and Th2 cell development in vivo. In this study, to address the role of costimulatory molecules CD27, CD30, 4-1BB, and OX40, which belong to the tumor necrosis factor receptor superfamily, in the development of Th1 and Th2 cells in vivo, we administered monoclonal antibody (mAb) against their ligands, CD70, CD30 ligand (L), 4-1BBL, and OX40L, to mice infected with L. major. Whereas anti-CD70, anti-CD30L, and anti–4-1BBL mAb exhibited no effect in either susceptible BALB/c or resistant C57BL/6 mice, the administration of anti-OX40L mAb abrogated progressive disease in BALB/c mice. Flow cytometric analysis indicated that OX40 was expressed on CD4+ T cells and OX40L was expressed on CD11c+ dendritic cells in the popliteal lymph nodes of L. major–infected BALB/c mice. In vitro stimulation of these CD4+ T cells showed that anti-OX40L mAb treatment resulted in substantially reduced production of Th2 cytokines. Moreover, this change in cytokine levels was associated with reduced levels of anti–L. major immunoglobulin (Ig)G1 and serum IgE. These results indicate that anti-OX40L mAb abrogated progressive leishmaniasis in BALB/c mice by suppressing the development of Th2 responses, substantiating a critical role of OX40–OX40L interaction in Th2 development in vivo.

scholarly journals Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection.

1994 ◽  
Vol 180 (4) ◽  
pp. 1273-1282 ◽  
Author(s):  
M B Graham ◽  
V L Braciale ◽  
T J Braciale
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Lymphocytes ◽  
Cd4 T Cells ◽  
Primary Role ◽  
T Helper ◽  
Helper Type

T lymphocytes play a primary role in recovery from viral infections and in antiviral immunity. Although viral-specific CD8+ and CD4+ T cells have been shown to be able to lyse virally infected targets in vitro and promote recovery from lethal infection in vivo, the role of CD4+ T lymphocytes and their mechanism(s) of action in viral immunity are not well understood. The ability to further dissect the role that CD4+ T cells play in the immune response to a number of pathogens has been greatly enhanced by evidence for more extensive heterogeneity among the CD4+ T lymphocytes. To further examine the role of CD4+ T cells in the immune response to influenza infection, we have generated influenza virus-specific CD4+ T cell clones from influenza-primed BALB/c mice with differential cytokine secretion profiles that are defined as T helper type 1 (Th1) clones by the production of interleukin 2 (IL-2) and interferon gamma (IFN-gamma), or as Th2 clones by the production of IL-4, IL-5, and IL-10. Our studies have revealed that Th1 clones are cytolytic in vitro and protective against lethal challenge with virus in vivo, whereas Th2 clones are noncytolytic and not protective. Upon further evaluation of these clonal populations we have shown that not only are the Th2 clones nonprotective, but that pulmonary pathology is exacerbated as compared with control mice as evidenced by delayed viral clearance and massive pulmonary eosinophilia. These data suggest that virus-specific CD4+ T cells of the Th2 subset may not play a primary role in virus clearance and recovery and may lead to immune mediated potentiation of injury.

scholarly journals Critical role of EBNA1-specific CD4+ T cells in the control of mouse Burkitt lymphoma in vivo

2004 ◽  
Vol 114 (4) ◽  
pp. 542-550 ◽  
Author(s):  
Tihui Fu ◽  
Kui Shin Voo ◽  
Rong-Fu Wang
Keyword(s):  
T Cells ◽  
Burkitt Lymphoma ◽  
Cd4 T Cells ◽  
Critical Role

scholarly journals Interleukin 4–Producing Cd4 T Cells Arise from Different Precursors Depending on the Conditions of Antigen Exposure in Vivo

2000 ◽  
Vol 191 (4) ◽  
pp. 683-694 ◽  
Author(s):  
Gilles Foucras ◽  
Laurent Gapin ◽  
Christiane Coureau ◽  
Jean M. Kanellopoulos ◽  
Jean-Charles Guéry
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Mouse Strains ◽  
Soluble Antigen ◽  
Th2 Response ◽  
Continuous Administration ◽  
Exposure In Vivo

The precursor origin of T helper (Th) cell subsets in vivo has been difficult to study and remains poorly investigated. We have previously shown that chronic administration of soluble protein antigen induces selective development of antigen-specific CD4 Th2 cells in genetically predisposed mouse strains. To analyze the origin of effector T cells in this model, we designed a competitive polymerase chain reaction–based approach to track public BV-J rearrangement expressed by CD4 T cells specific for hen egg white lysozyme (HEL) in BALB/c mice. We show that public T cell clones are predominantly associated with type 1 or 2 effector Th cells recovered after primary immunization in complete or incomplete Freund's adjuvant, respectively. Conversely, continuous administration of soluble antigen, which induces strong memory Th2 response, is associated with a dose-dependent reduction of public clone size by a mechanism resembling clonal anergy. Thus, soluble HEL–induced Th2 cells do not express the public complementarity determining region 3 motifs characteristic of immunogenic challenge in the presence of adjuvant. These results demonstrate that there are multiple pathways of induction of Th2 responses depending on the condition of antigen exposure in vivo, i.e., clonal immune deviation versus recruitment of a different pool of precursor cells.

scholarly journals Regulation of Interleukin (Il)-18 Receptor α Chain Expression on Cd4+ T Cells during T Helper (Th)1/Th2 Differentiation

2001 ◽  
Vol 194 (2) ◽  
pp. 143-154 ◽  
Author(s):  
Ronald B. Smeltz ◽  
June Chen ◽  
Jane Hu-Li ◽  
Ethan M. Shevach
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Th2 Cells ◽  
T Helper ◽  
Activated T Cells ◽  
T Cell Stimulation ◽  
Ifn Γ ◽  
Α Chain ◽  
Th 1

Interleukin (IL)-18 has been well characterized as a costimulatory factor for the induction of IL-12–mediated interferon (IFN)-γ production by T helper (Th)1 cells, but also can induce IL-4 production and thus facilitate the differentiation of Th2 cells. To determine the mechanisms by which IL-18 might regulate these diametrically distinct immune responses, we have analyzed the role of cytokines in the regulation of IL-18 receptor α chain (IL-18Rα) expression. The majority of peripheral CD4+ T cells constitutively expressed the IL-18Rα. Upon antigen stimulation in the presence of IL-12, marked enhancement of IL-18Rα expression was observed. IL-12–mediated upregulation of IL-18Rα required IFN-γ. Activated CD4+ T cells that expressed low levels of IL-18Rα could produce IFN-γ when stimulated with the combination of IL-12 and IL-18, while CD4+ cells which expressed high levels of IL-18Rα could respond to IL-18 alone. In contrast, T cell stimulation in the presence of IL-4 resulted in a downregulation of IL-18Rα expression. Both IL-4−/− and signal transducer and activator of transcription (Stat)6−/− T cells expressed higher levels of IL-18Rα after TCR stimulation. Furthermore, activated T cells from Stat6−/− mice produced more IFN-γ in response to IL-18 than wild-type controls. Thus, positive/negative regulation of the IL-18Rα by the major inductive cytokines (IL-12 and IL-4) determines the capacity of IL-18 to polarize an immune response.

scholarly journals 157 A critical role of CD40 and CD70 signaling in cDC1s in expansion and antitumor efficacy of adoptively transferred tumor-specific T cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A171-A171
Author(s):  
Takaaki Oba ◽  
Toshifumi Hoki ◽  
Takayoshi Yamauchi ◽  
Tibor Keler ◽  
Henry Marsh ◽  
...  
Keyword(s):  
T Cells ◽  
Adoptive Cell Therapy ◽  
Critical Role ◽  
Flow Cytometric Analysis ◽  
Antitumor Efficacy ◽  
Tumor Control ◽  
Type I ◽  
Loss Of Function

BackgroundAdoptive cell therapy (ACT) with antigen-specific CD8+ T cells is a promising approach for treating patients with various solid malignancies including melanoma. In vivo expansion of adoptively transferred T cells is one of the major determinants of successful ACT. On the other hand, a frequently overlooked consideration is that the host antigen-presenting cells affect the antitumor efficacy of ACT. Accumulating evidence suggests that tumor-residing Batf3-dependent conventional type I dendritic cells (cDC1s) play an important role in trafficking of adoptively transferred T cells into the tumor by producing chemokines such as CXCL10, and improve antitumor efficacy of ACT. However, a role of cDC1s in expansion of adoptively transferred T cells remains unclear.MethodsWe utilized Pmel-1 T cell receptor transgenic T cells in the B16 melanoma model to investigate the role of cDC1s in expansion of adoptively transferred tumor-specific T cells.ResultsWhile adoptive transfer of in vitro-activated Pmel-1 T cells with vaccination of cognate antigen, hgp100, agonistic anti-CD40 monoclonal antibody (mAb), and Toll-like receptor 7 (TLR7) agonist delayed the tumor growth and survival in wild type C57BL/6 mice (WT), antitumor efficacy of ACT was completely abrogated in Batf3-/- mice. Flow cytometric analysis of peripheral blood showed expansion of adoptively transferred Pmel-1 T cells was significantly compromised in WT mice but not in in Batf3-/- mice. Mechanistically, loss-of-function studies using mixed bone marrow chimera reconstituted with Batf3-/- and CD40-/- (Batf3-/-/CD40-/-), Batf3-/- and CD70-/- (Batf3-/-/CD70-/-), or Batf3-/- and CD80/86-/- (Batf3-/-/CD80/86-/-) revealed CD40-CD70 axis but not CD80/86 signaling in host cDC1s plays an important role in expansion of adoptively transferred T cells. Accordingly, overall survival of Batf3-/-/CD70-/- mixed chimeric was significantly shorter than that of Batf3-/-/WT mice, while survival of Batf3-/-/CD80/86-/- mice was similar to that of Batf3-/-/WT mice. Furthermore, induction of cDC1s by administration of Fms-like tyrosine kinase 3 receptor ligand (gain-of-function) demonstrated significantly enhanced in vivo expansion of adoptively transferred Pmel-1 T cells associated with improved tumor control and survival.ConclusionsThese findings elucidate a role of host cDC1s in expansion of adoptively transferred in vivo restimulated tumor-specific T cells, and identify CD40 and CD70 as key molecules.

scholarly journals Interferon γ Signaling Alters the Function of T Helper Type 1 Cells

2000 ◽  
Vol 192 (7) ◽  
pp. 977-986 ◽  
Author(s):  
Gregory Z. Tau ◽  
Thierry von der Weid ◽  
Binfeng Lu ◽  
Simone Cowan ◽  
Marina Kvatyuk ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Interferon Γ ◽  
Delayed Type Hypersensitivity ◽  
Th2 Cells ◽  
Th1 Cells ◽  
T Helper ◽  
Ifn Γ ◽  
And Function

One mechanism regulating the ability of different subsets of T helper (Th) cells to respond to cytokines is the differential expression of cytokine receptors. For example, Th2 cells express both chains of the interferon γ receptor (IFN-γR), whereas Th1 cells do not express the second chain of the IFN-γR (IFN-γR2) and are therefore unresponsive to IFN-γ. To determine whether the regulation of IFN-γR2 expression, and therefore IFN-γ responsiveness, is important for the differentiation of naive CD4+ T cells into Th1 cells or for Th1 effector function, we generated mice in which transgenic (TG) expression of IFN-γR2 is controlled by the CD2 promoter and enhancer. CD4+ T cells from IFN-γR2 TG mice exhibit impaired Th1 polarization potential in vitro. TG mice also display several defects in Th1-dependent immunity in vivo, including attenuated delayed-type hypersensitivity responses and decreased antigen-specific IFN-γ production. In addition, TG mice mount impaired Th1 responses against Leishmania major, as manifested by increased parasitemia and more severe lesions than their wild-type littermates. Together, these data suggest that the sustained expression of IFN-γR2 inhibits Th1 differentiation and function. Therefore, the acquisition of an IFN-γ–unresponsive phenotype in Th1 cells plays a crucial role in the development and function of these cells.

scholarly journals Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations

2011 ◽  
Vol 208 (4) ◽  
pp. 797-809 ◽  
Author(s):  
Pejman Soroosh ◽  
Taylor A. Doherty ◽  
Takanori So ◽  
Amit Kumar Mehta ◽  
Naseem Khorram ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Th2 Cells ◽  
Memory Cells ◽  
T Helper ◽  
Recall Antigen ◽  
Memory Cd4 T Cells ◽  
Herpesvirus Entry Mediator

Memory T helper cells (Th cells) play an important role in host defense against pathogens but also contribute to the pathogenesis of inflammatory disorders. We found that a soluble decoy lymphotoxin β receptor (LT-βR)–Fc, which can block tumor necrosis factor (TNF)–related ligands LIGHT (TNFSF14) and LT-αβ binding to the herpesvirus entry mediator (HVEM) and the LT-βR, inhibited the accumulation of memory Th2 cells after antigen encounter and correspondingly reduced inflammatory responses in vivo. Showing that this was a function of the receptor for LIGHT, antigen-specific memory CD4 T cells deficient in HVEM were also unable to persist, despite having a normal immediate response to recall antigen. HVEM−/− memory Th2 cells displayed reduced activity of PKB (protein kinase B; Akt), and constitutively active Akt rescued their survival and restored strong inflammation after antigen rechallenge. This was not restricted to Th2 memory cells as HVEM-deficient Th1 memory cells were also impaired in surviving after encounter with recall antigen. Furthermore, the absence of LIGHT on T cells recapitulated the defect seen with the absence of HVEM, suggesting that activated T cells communicate through LIGHT–HVEM interactions. Collectively, our results demonstrate a critical role of HVEM signals in the persistence of large pools of memory CD4 T cells.

scholarly journals Rapid Development of Th2 Activity During T Cell Priming

2003 ◽  
Vol 10 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Adam F. Cunningham ◽  
Kai-Michael Toellner
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rapid Development ◽  
Critical Role ◽  
Cell Polarization ◽  
Th2 Cells ◽  
Th1 Cells ◽  
T Helper ◽  
Th 1 ◽  
Th1 And Th2

The paradigm of T helper-1 (Th-1) and Th-2 cells developing from non-committed naïve precursors is firmly established. Th1 cells are characterized by IFN production and, in mice, the selective switching to IgG2a. Conversely IL-4 production and selective switching to IgG1 and IgE characterize Th2 cells. Analysis of Th2 inductionin vitroindicates that this polarization develops gradually in T cells activated by anti-CD3 in the presence of IL-4; conversely anti-CD3 and IFN induce Th1 cells. In this report, we explore evidence that indicates that the T helper cell polarizationin vivocannot solely be explained by the cytokine environment. This is provided by studying the early acquisition of Th1 and Th2 activities during responses to a mixture of Th1 and Th2-inducing antigens. It is shown that these divergent forms of T cell help can rapidly develop in cells within a single lymph node. It is argued that early polarization to show Th-1 or Th-2 behavior can be induced by signals delivered during cognate interaction between virgin T cells and dendritic cells, in the absence of type 1 or type 2 cytokines. This contrasts with the critical role of the cytokines in reinforcing the Th-phenotype and selectively expanding T helper clones.

scholarly journals 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.

1994 ◽  
Vol 179 (4) ◽  
pp. 1273-1283 ◽  
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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