Faculty Opinions recommendation of Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major.

Mice with homologous disruption of the interferon gamma (IFN-gamma) gene on the C57BL/6 background were infected with Leishmania major and the immune response assessed. In contrast to wild-type or heterozygous knockout mice, deficient animals were unable to restrict growth of the parasite and suffered lethal infection over 6-8 wk. Although wild-type and heterozygous littermates developed CD4+ cells that contained transcripts for IFN-gamma and lymphotoxin, typical of T helper type 1 (Th1) cells, the knockout mice developed CD4+ cells that contained transcripts for interleukin 4 (IL-4), IL-5, and IL-13, typical of Th2 cells. ELISPOT assays confirmed the reciprocal patterns of IFN-gamma or IL-4 production by T cells in similar frequencies in the respective groups of mice, and antibody analysis confirmed the presence of Th2-mediated isotype switching in the knockout mice. These data suggest that CD4+ T cells that normally respond to antigens by differentiation to Th1 cells default to the Th2 pathway in the absence of endogenous IFN-gamma.

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Listeria monocytogenes as a Short-Lived Delivery System for the Induction of Type 1 Cell-Mediated Immunity against the p36/LACK Antigen of Leishmania major

Infection and Immunity ◽

10.1128/iai.68.3.1498-1506.2000 ◽

2000 ◽

Vol 68 (3) ◽

pp. 1498-1506 ◽

Cited By ~ 35

Author(s):

Neirouz Soussi ◽

Geneviève Milon ◽

Jean-Hervé Colle ◽

Evelyne Mougneau ◽

Nicolas Glaichenhaus ◽

...

Keyword(s):

T Cells ◽

Listeria Monocytogenes ◽

Cd4 T Cells ◽

Leishmania Major ◽

Ex Vivo ◽

Experimental Models ◽

Interleukin 4 ◽

Cell Mediated Immunity ◽

Th1 Cells ◽

Ifn Γ

ABSTRACT Listeria monocytogenes has been used as an experimental live vector for the induction of CD8-mediated immune responses in various viral and tumoral experimental models. Susceptibility of BALB/c mice to Leishmania major infection has been correlated to the preferential development of Th2 CD4 T cells through an early production of interleukin 4 (IL-4) by a restricted population of CD4 T cells which react to a single parasite antigen, LACK (stands forLeishmania homologue of receptors for activated C kinase). Experimental vaccination with LACK can redirect the differentiation of CD4+ T cells towards the Th1 pathway if LACK is coadministrated with IL-12. As IL-12 is known to be induced by L. monocytogenes, we have tested the ability of a recombinant attenuated actA mutant L. monocytogenes strain expressing LACK to induce the development of LACK-specific Th1 cells in both B10.D2 and BALB/c mice, which are resistant and susceptible toL. major, respectively. After a single injection of LACK-expressing L. monocytogenes, IL-12/p40 transcripts showed a rapid burst, and peaks of gamma interferon (IFN-γ)-secreting LACK-specific Th1 cells were detected around day 5 in the spleens and livers of mice of both strains. These primed IFN-γ-secreting LACK-reactive T cells were not detected ex vivo after day 7 of immunization but could be recruited and detected 15 days later in the draining lymph node after an L. major footpad challenge. Although immunization of BALB/c mice with LACK-expressing L. monocytogenes did not change the course of the infection withL. major, immunized B10.D2 mice exhibited significantly smaller lesions than nonimmunized controls. Thus, our results demonstrate that, in addition of its recognized use for the induction of effector CD8 T cells, L. monocytogenes can also be used as a live recombinant vector to favor the development of potentially protective IFN-γ-secreting Th1 CD4 T lymphocytes.

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Protective CD4+ Th1 cell-mediated immunity is reliant upon execution of effector function prior to the establishment of the pathogen niche

PLoS Pathogens ◽

10.1371/journal.ppat.1009944 ◽

2021 ◽

Vol 17 (9) ◽

pp. e1009944

Author(s):

Leah S. Hohman ◽

Zhirong Mou ◽

Matheus B. Carneiro ◽

Gabriel Ferland ◽

Rachel M. Kratofil ◽

...

Keyword(s):

Leishmania Major ◽

Host Cells ◽

Secondary Site ◽

Cell Mediated Immunity ◽

Th1 Cells ◽

T Helper 1 ◽

Th1 Cell ◽

Inflammatory Monocytes ◽

Adaptive Immune Cells ◽

Concomitant Immunity

Intracellular infection with the parasite Leishmania major features a state of concomitant immunity in which CD4+ T helper 1 (Th1) cell-mediated immunity against reinfection coincides with a chronic but sub-clinical primary infection. In this setting, the rapidity of the Th1 response at a secondary site of challenge in the skin represents the best correlate of parasite elimination and has been associated with a reversal in Leishmania-mediated modulation of monocytic host cells. Remarkably, the degree to which Th1 cells are absolutely reliant upon the time at which they interact with infected monocytes to mediate their protective effect has not been defined. In the present work, we report that CXCR3-dependent recruitment of Ly6C+ Th1 effector (Th1EFF) cells is indispensable for concomitant immunity and acute (<4 days post-infection) Th1EFF cell-phagocyte interactions are critical to prevent the establishment of a permissive pathogen niche, as evidenced by altered recruitment, gene expression and functional capacity of innate and adaptive immune cells at the site of secondary challenge. Surprisingly, provision of Th1EFF cells after establishment of the pathogen niche, even when Th1 cells were provided in large quantities, abrogated protection, Th1EFF cell accumulation and IFN-γ production, and iNOS production by inflammatory monocytes. These findings indicate that protective Th1 immunity is critically dependent on activation of permissive phagocytic host cells by preactivated Th1EFF cells at the time of infection.

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

Journal of Experimental Medicine ◽

10.1084/jem.192.7.977 ◽

2000 ◽

Vol 192 (7) ◽

pp. 977-986 ◽

Cited By ~ 36

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.

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Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4.

Journal of Experimental Medicine ◽

10.1084/jem.181.5.1755 ◽

1995 ◽

Vol 181 (5) ◽

pp. 1755-1762 ◽

Cited By ~ 454

Author(s):

N G Jacobson ◽

S J Szabo ◽

R M Weber-Nordt ◽

Z Zhong ◽

R D Schreiber ◽

...

Keyword(s):

T Cells ◽

Leishmania Major ◽

Nuclear Dna ◽

Interleukin 12 ◽

Th1 Cells ◽

T Helper ◽

Natural Ligand ◽

Nuclear Factors ◽

Helper Type

Interleukin 12 (IL-12) initiates the differentiation of naive CD4+ T cells to T helper type 1 (Th1) cells critical for resistance to intracellular pathogens such as Leishmania major. To explore the basis of IL-12 action, we analyzed induction of nuclear factors in Th1 cells. IL-12 selectively induced nuclear DNA-binding complexes that contained Stat3 and Stat4, recently cloned members of the family of signal transducers and activators of transcription (STATs). While Stat3 participates in signaling for several other cytokines, Stat4 was not previously known to participate in the signaling pathway for any natural ligand. The selective activation of Stat4 provides a basis for unique actions of IL-12 on Th1 development. Thus, this study presents the first identification of the early events in IL-12 signaling in T cells and of ligand activation of Stat4.

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Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major

Yearbook of Dermatology and Dermatologic Surgery ◽

10.1016/s0093-3619(08)70811-6 ◽

2008 ◽

Vol 2008 ◽

pp. 176-177 ◽

Cited By ~ 1

Author(s):

B.H. Thiers

Keyword(s):

Leishmania Major ◽

Th1 Cells

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CD4+CD25−Foxp3− Th1 cells are the source of IL-10–mediated immune suppression in chronic cutaneous leishmaniasis

Journal of Experimental Medicine ◽

10.1084/jem.20061886 ◽

2007 ◽

Vol 204 (2) ◽

pp. 285-297 ◽

Cited By ~ 400

Author(s):

Charles F. Anderson ◽

Mohammed Oukka ◽

Vijay J. Kuchroo ◽

David Sacks

Keyword(s):

T Cells ◽

Immune Suppression ◽

Leishmania Major ◽

T Regulatory Cells ◽

Th1 Cells ◽

Chronic Infections ◽

Th1 Cell ◽

Relative Contribution ◽

Severe Infections

Nonhealing forms of leishmaniasis in humans are commonly associated with elevated levels of the deactivating cytokine IL-10, and in the mouse, normally chronic infections can be cleared in the absence of IL-10. Using a Leishmania major strain that produces nonhealing dermal lesions in a T helper type 1 (Th1) cell–polarized setting, we have analyzed the cellular sources of IL-10 and their relative contribution to immune suppression. IL-10 was produced by innate cells, as well as CD4+CD25+Foxp3+ and CD4+CD25−Foxp3− T cells in the chronic lesion. Nonetheless, only IL-10 production by antigen-specific CD4+CD25−Foxp3− T cells, the majority of which also produced IFN-γ, was necessary for suppression of acquired immunity in Rag−/− reconstituted mice. Surprisingly, Rag−/− mice reconstituted with naive CD4+ T cells depleted of natural T regulatory cells developed more severe infections, associated with elevated levels of IL-10 and, especially, Th2 cytokines in the site. The data demonstrate that IL-10–producing Th1 cells, activated early in a strong inflammatory setting as a mechanism of feedback control, are the principal mediators of T cell–derived IL-10–dependent immune suppression in a chronic intracellular infection.

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Differential Production of Macrophage Inflammatory Protein 1γ (MIP-1γ), Lymphotactin, and MIP-2 by CD4+ Th Subsets Polarized In Vitro and In Vivo

Infection and Immunity ◽

10.1128/iai.71.11.6178-6183.2003 ◽

2003 ◽

Vol 71 (11) ◽

pp. 6178-6183 ◽

Cited By ~ 20

Author(s):

Kerstin Müller ◽

Susanne Bischof ◽

Frank Sommer ◽

Michael Lohoff ◽

Werner Solbach ◽

...

Keyword(s):

Leishmania Major ◽

Th2 Cells ◽

Infection Model ◽

Th1 Cells ◽

Th Cells ◽

Inflammatory Protein ◽

Macrophage Inflammatory Protein ◽

Th1 And Th2

ABSTRACT Due to differential expression of chemokine receptors, the Th1 and Th2 subsets of CD4+ T cells differ in their migratory responses to chemokines. These differences in the migration patterns are likely to play a role in the initiation and regulation of Th1 and Th2 immune responses, inflammatory processes, and T-cell-mediated pathology. In the present study we evaluated the role of activated Th cells as producers of chemokines. Three different sources of murine Th cells were used, i.e., long-term-cultured Th1 and Th2 cell clones, Th1 and Th2 cells differentiated from naïve CD4+ spleen and lymph node cells in vitro, and Th1 and Th2 subsets polarized in vivo using a murine experimental Leishmania major infection model. Following stimulation with anti-CD3, macrophage inflammatory protein 1γ (MIP-1γ) and lymphotactin were produced selectively by Th1 cells but not by Th2 cells. In contrast, only Th2 cells produced MIP-2. The possible biological relevance of these data was substantiated by the finding that in vivo-polarized Th1 cells, but not Th2 cells, produced MIP-1γ and lymphotactin while in vivo-polarized Th2 cells secreted MIP-2. The above data demonstrate that Th1 and Th2 cells differ in their ability to produce chemokines, suggesting that Th1 and Th2 subsets differentially contribute to recruitment of cells into inflammatory foci.

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