scholarly journals The Leishmania major LACK Antigen with an Immunodominant Epitope at Amino Acids 156 to 173 Is Not Required for Early Th2 Development in BALB/c Mice

2004 ◽  
Vol 72 (12) ◽  
pp. 6924-6931 ◽  
Author(s):  
Ben L. Kelly ◽  
Richard M. Locksley
Keyword(s):  
Amino Acids ◽  
T Cells ◽  
Leishmania Major ◽  
Cell Receptor ◽  
Interleukin 4 ◽  
Wild Type ◽  
Immunodominant Epitope ◽  
Fusion Construct ◽  
Th2 Immune Response

ABSTRACT The Leishmania major LACK antigen contains an immunodominant epitope at amino acids 156 to 173 (LACK156-173) that is believed to nucleate the pathological Th2 immune response in susceptible BALB/c mice. To test this hypothesis, we generated L. major parasites that express a mutated LACK that fails to activate Vβ4/Vα8 T-cell receptor transgenic T cells specific for this epitope. Although mutant parasites attenuated the expansion of endogenous LACK-specific, interleukin-4 (IL-4)-expressing, CD4 T cells compared to wild-type parasites in vivo, the overall frequency of IL-4 and gamma interferon-secreting lymphocytes was similar to that elicited by wild-type L. major. Mutant parasites demonstrated diminished amastigote viability and delayed lesion development in mice, although parasites could be recovered over 200 days after infection. Complementation with a wild-type lack fusion construct partially rescued these defects, indicating a role for endogenous LACK in parasitism. Mice inoculated with mutant parasites were not protected against subsequent infection with wild-type L. major.

scholarly journals CD4+ effector cells default to the Th2 pathway in interferon gamma-deficient mice infected with Leishmania major.

1994 ◽  
Vol 179 (4) ◽  
pp. 1367-1371 ◽  
Author(s):  
Z E Wang ◽  
S L Reiner ◽  
S Zheng ◽  
D K Dalton ◽  
R M Locksley
Keyword(s):  
T Cells ◽  
Interferon Gamma ◽  
Knockout Mice ◽  
Leishmania Major ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Wild Type ◽  
Cd4 Cells ◽  
Ifn Gamma

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.

scholarly journals Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism.

1990 ◽  
Vol 171 (1) ◽  
pp. 115-127 ◽  
Author(s):  
M D Sadick ◽  
F P Heinzel ◽  
B J Holaday ◽  
R T Pu ◽  
R S Dawkins ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Leishmania Major ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Lymphoid Tissues ◽  
Ifn Gamma ◽  
Fourfold Increase ◽  
Cd8 Cells

BALB/c mice infected with Leishmania major develop fatal, progressive disease, despite an immune response characterized by expansion of CD4+ T cells in the draining lymph nodes. The immune response has been further characterized by a lack of IFN-gamma mRNA, but increased IL-4 mRNA in lymphoid tissues, and striking elevation of serum IgE. Treatment of infected BALB/c mice with rIFN-gamma at doses shown to be beneficial in other protozoan infections was insufficient to ameliorate L. major infection. In contrast, neutralization of IL-4 by six weekly injections of mAb 11B11 led to attenuation of disease in 100% of animals, and complete cure in 85%. Resolution of disease required the presence of T cells, and recovered mice remained resistant to reinfection at 12 wk. This immunity was adoptively transferable and was dependent on both CD4+ and CD8+ cells. Although administration of anti-IL-4 was associated with fourfold increase in IFN-gamma mRNA in lymph node cells draining the lesion, the coadministration of neutralizing R4 6A2 anti-IFN-gamma mAb had no effect on resistance to disease. This was in marked contrast to resolution of disease in both resistant C57BL/6- and GK1.5-pretreated BALB/c mice that was abrogated by in vivo treatment with anti-IFN-gamma. These data suggest a novel mechanism of cellular immunity established by interference with the development of Th2 cells during infection.

scholarly journals Tracking the Response of Natural Killer T Cells to a Glycolipid Antigen Using Cd1d Tetramers

2000 ◽  
Vol 192 (5) ◽  
pp. 741-754 ◽  
Author(s):  
Jennifer L. Matsuda ◽  
Olga V. Naidenko ◽  
Laurent Gapin ◽  
Toshinori Nakayama ◽  
Masaru Taniguchi ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Cell Number ◽  
Interleukin 4 ◽  
Regulatory Function ◽  
Nk T Cells ◽  
Lipid Antigen

A major group of natural killer (NK) T cells express an invariant Vα14+ T cell receptor (TCR) specific for the lipoglycan α-galactosylceramide (α-GalCer), which is presented by CD1d. These cells may have an important immune regulatory function, but an understanding of their biology has been hampered by the lack of suitable reagents for tracking them in vivo. Here we show that tetramers of mouse CD1d loaded with α-GalCer are a sensitive and highly specific reagent for identifying Vα14+ NK T cells. Using these tetramers, we find that α-GalCer–specific T lymphocytes are more widely distributed than was previously appreciated, with populations of largely NK1.1− but tetramer-binding T cells present in the lymph nodes and the intestine. Injection of α-GalCer leads to the production of both interferon γ and interleukin 4 by nearly all NK T cells in the liver and the majority of the spleen within 2 h. These cells mostly disappear by 5 h, and they do not reappear after 1 wk. Curiously, tetramer-positive thymocytes do not rapidly synthesize cytokines, nor do they undergo decreases in cell number after lipid antigen stimulation, although they express equivalent TCR levels. In summary, the data presented here demonstrate that α-GalCer–specific NK T cells undergo a unique and highly compartmentalized response to antigenic stimulation.

scholarly journals T-Cell Responses to Immunodominant LACK Antigen Do Not Play a Critical Role in Determining Susceptibility of BALB/c Mice toLeishmania mexicana

2001 ◽  
Vol 69 (1) ◽  
pp. 617-621 ◽  
Author(s):  
Fabiola Aguilar Torrentera ◽  
Nicolas Glaichenhaus ◽  
Jon D. Laman ◽  
Yves Carlier
Keyword(s):  
T Cells ◽  
T Cell ◽  
Leishmania Major ◽  
Critical Role ◽  
Interleukin 4 ◽  
Hybridoma Cells ◽  
Leishmania Mexicana ◽  
Wild Type ◽  
Cell Responses ◽  
Early Production

ABSTRACT Although BALB/c mice develop lesions when infected withLeishmania mexicana, the mechanisms which are responsible for susceptibility to this parasite have not been elucidated. In contrast, susceptibility of BALB/c mice to Leishmania majorhas been shown to depend on the early production of interleukin-4 (IL-4) by T cells which react to the parasitic LACK antigen. Here, we demonstrate that the lesions induced by L. mexicana are delayed compared to those induced by L. major but rapidly develop at later time points. Interestingly, while LACK-tolerant BALB/c-derived IE-LACK transgenic mice were resistant to L. major, they were susceptible to L. mexicana and developed lesions similar to those observed in wild-type BALB/c mice. The latter result was observed despite the fact that (i) LACK was expressed by L. mexicana, (ii) splenocytes from BALB/c mice were able to stimulate LACK-specific T-cell hybridoma cells when incubated with live L. mexicana promastigotes, and (iii) LACK-specific T cells contributed to IL-4 production in L. mexicana-infected BALB/c mice. Thus, in contrast to what was observed for L. major-infected mice, LACK-specific T cells do not play a critical role in determining susceptibility to L. mexicana. Although BALB/c mice are susceptible to both L. major and L. mexicana, the mechanisms which are responsible for susceptibility to these parasites are likely to be different.

scholarly journals Nasopharyngeal infection byStreptococcus pyogenesrequires superantigen-responsive Vβ-specific T cells

2017 ◽  
Vol 114 (38) ◽  
pp. 10226-10231 ◽  
Author(s):  
Joseph J. Zeppa ◽  
Katherine J. Kasper ◽  
Ivor Mohorovic ◽  
Delfina M. Mazzuca ◽  
S. M. Mansour Haeryfar ◽  
...  
Keyword(s):  
T Cells ◽  
High Titer ◽  
Passive Immunization ◽  
Cell Receptor ◽  
Active Immunization ◽  
Wild Type ◽  
Toxic Shock ◽  
Variable Domains ◽  
Β Chain

The globally prominent pathogenStreptococcus pyogenessecretes potent immunomodulatory proteins known as superantigens (SAgs), which engage lateral surfaces of major histocompatibility class II molecules and T-cell receptor (TCR) β-chain variable domains (Vβs). These interactions result in the activation of numerous Vβ-specific T cells, which is the defining activity of a SAg. Although streptococcal SAgs are known virulence factors in scarlet fever and toxic shock syndrome, mechanisms by how SAgs contribute to the life cycle ofS. pyogenesremain poorly understood. Herein, we demonstrate that passive immunization against the Vβ8-targeting SAg streptococcal pyrogenic exotoxin A (SpeA), or active immunization with either wild-type or a nonfunctional SpeA mutant, protects mice from nasopharyngeal infection; however, only passive immunization, or vaccination with inactive SpeA, resulted in high-titer SpeA-specific antibodies in vivo. Mice vaccinated with wild-type SpeA rendered Vβ8+T cells poorly responsive, which prevented infection. This phenotype was reproduced with staphylococcal enterotoxin B, a heterologous SAg that also targets Vβ8+T cells, and rendered mice resistant to infection. Furthermore, antibody-mediated depletion of T cells prevented nasopharyngeal infection byS. pyogenes, but not byStreptococcus pneumoniae, a bacterium that does not produce SAgs. Remarkably, these observations suggest thatS. pyogenesuses SAgs to manipulate Vβ-specific T cells to establish nasopharyngeal infection.

scholarly journals T cell genetic background determines default T helper phenotype development in vitro.

1995 ◽  
Vol 181 (2) ◽  
pp. 713-721 ◽  
Author(s):  
C S Hsieh ◽  
S E Macatonia ◽  
A O'Garra ◽  
K M Murphy
Keyword(s):  
T Cells ◽  
T Cell ◽  
Genetic Background ◽  
Leishmania Major ◽  
Cell Receptor ◽  
T Helper ◽  
Alpha Beta ◽  
Development In Vitro

A host's ability to resist certain pathogens such as Leishmania major can depend upon the phenotype of T helper (Th) subset that develops. Different murine genetic backgrounds are known to significantly alter the direction of Th subset development, although the cellular basis of this influence is poorly understood. To examine the basis of this effect we used an in vitro alpha/beta-T cell receptor (TCR) transgenic system for analysis of Th phenotype development. To control for TCR usage, we derived the DO11.10 alpha/beta-TCR transgene in several genetic backgrounds. Our findings suggest that the effects of genetic background on Th phenotype development reside within the T cell, and not the antigen-presenting cell compartment. Transgenic T cells from both the B10.D2 and BALB/c backgrounds showed development toward either the Th1 or Th2 phenotype under the strong directing influence of interleukin (IL) 12 and IL4, respectively. However, when T cells were activated in vitro under neutral conditions in which exogenous cytokines were not added, B10.D2-derived T cells acquired a significantly stronger Th1 phenotype than T cells from the BALB/c background, correspondent with in vivo Th responses to Leishmania in these strains. Importantly, these cytokine differences resulted in distinct functional properties, because B10.D2- but not BALB/c-derived T cells could induce macrophage production of nitric oxide, an important antimicrobial factor. Thus, the genetically determined default Th phenotype development observed in vitro may correspond to in vivo Th subset responses for pathogens such as Leishmania which do not initiate strong Th phenotype-directing signals.

scholarly journals A subset of dendritic cells induces CD4+ T cells to produce IFN-γ by an IL-12–independent but CD70-dependent mechanism in vivo

2007 ◽  
Vol 204 (5) ◽  
pp. 1095-1106 ◽  
Author(s):  
Helena Soares ◽  
HaeNa Waechter ◽  
Nicholas Glaichenhaus ◽  
Evelyne Mougneau ◽  
Hideo Yagita ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Cell Receptor ◽  
In Vivo Detection ◽  
Ifn Γ ◽  
Resistance To Infection

Interferon (IFN)-γ, a cytokine critical for resistance to infection and tumors, is produced by CD4+ helper T lymphocytes after stimulation by cultured dendritic cells (DCs) that secrete a cofactor, interleukin (IL)-12. We have identified a major IL-12–independent pathway whereby DCs induce IFN-γ–secreting T helper (Th)1 CD4+ T cells in vivo. This pathway requires the membrane-associated tumor necrosis family member CD70 and was identified by targeting the LACK antigen from Leishmania major within an antibody to CD205 (DEC-205), an uptake receptor on a subset of DCs. Another major DC subset, targeted with 33D1 anti-DCIR2 antibody, also induced IFN-γ in vivo but required IL-12, not CD70. Isolated CD205+ DCs expressed cell surface CD70 when presenting antigen to T cell receptor transgenic T cells, and this distinction was independent of maturation stimuli. CD70 was also essential for CD205+ DC function in vivo. Detection of the IL-12–independent IFN-γ pathway was obscured with nontargeted LACK, which was presented by both DC subsets. This in situ analysis points to CD70 as a decision maker for Th1 differentiation by CD205+ DCs, even in Th2-prone BALB/c animals and potentially in vaccine design. The results indicate that two DC subsets have innate propensities to differentially affect the Th1/Th2 balance in vivo and by distinct mechanisms.

scholarly journals Interleukin 4 expressed in situ selectively alters thymocyte development.

1991 ◽  
Vol 173 (1) ◽  
pp. 89-100 ◽  
Author(s):  
D B Lewis ◽  
C C Yu ◽  
K A Forbush ◽  
J Carpenter ◽  
T A Sato ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Interleukin 4 ◽  
Thymocyte Development ◽  
Double Positive ◽  
Peripheral T Cells ◽  
Single Positive ◽  
And Control

Using a transgenic mouse model we show that increased intrathymic expression of interleukin 4 (IL-4) significantly perturbs the development of thymocytes. Transgenic double-positive (CD4+CD8+) thymocytes, which are present in dramatically reduced numbers, exhibit increased T cell receptor (TCR) expression and increased mobilization of calcium mediated by these receptors. In contrast, transgenic single-positive (CD4+CD8- and CD4-CD8+) thymocytes and peripheral T cells exhibit decreased TCR-mediated calcium mobilization. The development of CD4-CD8+ thymocytes is significantly perturbed by IL-4 expressed in vivo; only peripheral CD4+ T cells are found in significant numbers in transgenic mice, while CD4-CD8+ thymocytes are present in increased numbers, apparently because of their failure to emigrate to the periphery. In contrast to these selective effects on T cell development, no significant differences in the numbers of B cells or mast cells, or in the plasma levels of IgE and IgG1 are observed between transgenic and control mice. These observations suggest that IL-4 in vivo exerts its major effects locally rather than systemically, even when its expression is constitutively increased.

scholarly journals Disruption of Mekk2 in Mice Reveals an Unexpected Role for MEKK2 in Modulating T-Cell Receptor Signal Transduction

2002 ◽  
Vol 22 (16) ◽  
pp. 5761-5768 ◽  
Author(s):  
Zijian Guo ◽  
Gavin Clydesdale ◽  
Jinke Cheng ◽  
Kihwan Kim ◽  
Lin Gan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Wild Type ◽  
Kinase Gene

ABSTRACT MEKK2 is a member of the mitogen-activated protein kinase (MAPK) kinase kinase gene family involved in regulating multiple MAPK signaling pathways. To elucidate the in vivo function of MEKK2, we generated mice carrying a targeted mutation in the Mekk2 locus. Mekk2 −/− mice are viable and fertile. Major subsets of thymic and spleen T cells in Mekk2-deficient mice were indistinguishable from those in wild-type mice. B-cell development appeared to proceed similarly in the bone marrow of Mekk2-deficient and wild-type mice. However, Mekk2 −/− T-cell proliferation was augmented in response to anti-CD3 monoclonal antibody (MAb) stimulation, and these T cells produced more interleukin 2 and gamma interferon than did the wild-type T cells, suggesting that MEKK2 may be involved in controlling the strength of T-cell receptor (TCR) signaling. Consistently, Mekk2 −/− thymocytes were more susceptible than wild-type thymocytes to anti-CD3 MAb-induced cell death. Furthermore, TCR-mediated c-Jun N-terminal kinase activation was not blocked but moderately enhanced in Mekk2 −/− T cells. Neither extracellular signal-regulated kinase nor p38 MAPK activation was affected in Mekk2 −/− T cells. In conclusion, we found that MEKK2 may be required for controlling the strength of TCR/CD3 signaling.

scholarly journals T-Cell-Dependent Control of Acute Giardia lamblia Infections in Mice

2000 ◽  
Vol 68 (1) ◽  
pp. 170-175 ◽  
Author(s):  
Steven M. Singer ◽  
Theodore E. Nash
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Giardia Lamblia ◽  
Cell Receptor ◽  
Interleukin 4 ◽  
Wild Type ◽  
Adult Mice ◽  
Giardia Muris ◽  
Deficient Mice

ABSTRACTWe have studied immune mechanisms responsible for control of acuteGiardia lambliaandGiardia murisinfections in adult mice. Association of chronicG. lambliainfection with hypogammaglobulinemia and experimental infections of mice withG. murishave led to the hypothesis that antibodies are required to control these infections. We directly tested this hypothesis by infecting B-cell-deficient mice with eitherG. lambliaorG. muris. Both wild-type mice and B-cell-deficient mice eliminated the vast majority of parasites between 1 and 2 weeks postinfection withG. lamblia. G. muriswas also eliminated in both wild-type and B-cell-deficient mice. In contrast, T-cell-deficient andscidmice failed to controlG. lambliainfections, as has been shown previously forG. muris. Treatment of wild-type or B-cell-deficient mice with antibodies to CD4 also prevented elimination ofG. lamblia, confirming a role for T cells in controlling infections. By infecting mice deficient in either αβ- or γδ-T-cell receptor (TCR)-expressing T cells, we show that the αβ-TCR-expressing T cells are required to control parasites but that the γδ-TCR-expressing T cells are not. Finally, infections in mice deficient in production of gamma interferon or interleukin 4 (IL-4) and mice deficient in responding to IL-4 and IL-13 revealed that neither the Th1 nor the Th2 subset is absolutely required for protection fromG. lamblia. We conclude that a T-cell-dependent mechanism is essential for controlling acuteGiardiainfections and that this mechanism is independent of antibody and B cells.

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