A repetitive peptide of Leishmania can activate T helper type 2 cells and enhance disease progression.

Leishmaniasis provides a biologically relevant model to analyze the heterogeneity of CD4+ T cells and may lead to answering the major question of the mechanism for the preferential induction of T helper type 1 (Th1) and Th2 cells. Using synthetic peptides corresponding to the tandemly repeating regions of Leishmania proteins, we have identified an epitope that can preferentially induce the disease-exacerbating Th2 cells in susceptible BALB/c mice. Lymph node cells from BALB/c mice immunized subcutaneously with the octamer (p183) of the repeating 10-mer peptide EAEEAARLQA proliferated strongly against the peptide as well as the soluble antigen extract (SolAg) of Leishmania major. The proliferative T cells are CD4+, major histocompatibility complex class II restricted, and secrete interleukin 4 (IL-4) but little or no IL-2 and interferon gamma when stimulated with the peptide in vitro. T cells from BALB/c mice with progressive disease, but not from BALB/c mice cured of the infection, recognized this epitope. BALB/c mice injected subcutaneously with p183 developed significantly exacerbated disease when subsequently challenged with L. major. Furthermore, subcutaneous injection with p183 prevented the subsequent induction of resistance against L. major by intravenous immunization with soluble antigen. The T cell response to p183 is H-2d restricted. Immunization of the genetically resistant B10.D2 mice with p183 also produced strong T cell responses and exacerbated disease when challenged with L. major.

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T-cell response to bacterial agents

The Journal of Infection in Developing Countries ◽

10.3855/jidc.2019 ◽

2011 ◽

Vol 5 (09) ◽

pp. 640-645 ◽

Cited By ~ 36

Author(s):

Mario Milco D'Elios ◽

Marisa Benagiano ◽

Chiara Della Bella ◽

Amedeo Amedei

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Response ◽

Th2 Cells ◽

T Helper ◽

T Helper 1 ◽

Cell Responses ◽

Genetic And Environmental Factors ◽

Bacteria And Fungi ◽

Antigen Presenting

T-cell responses are crucial for the outcome of any infection. The type of effector T-cell reaction is determined by a complex interaction of antigen-presenting cells with naive T cells and involves genetic and environmental factors, including the type of antigen, cytokines, chemokines, co-stimulatory molecules, and signalling cascades. The decision for the immune response to go in a certain direction is based not on one signal alone, but rather on many different elements acting both synergistically and antagonistically, and through feedback loops leading to activation or inhibition of T cells. In the course of evolution different types of T cells have developed, such as T helper 1 (Th1) cells, which protect against intracellular bacteria; Th2 cells, which play a role against parasites; and Th17 cells, which face extracellular bacteria and fungi

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Recent thymic emigrants are biased against the T-helper type 1 and toward the T-helper type 2 effector lineage

Blood ◽

10.1182/blood-2010-07-299263 ◽

2011 ◽

Vol 117 (4) ◽

pp. 1239-1249 ◽

Cited By ~ 40

Author(s):

Deborah W. Hendricks ◽

Pamela J. Fink

Keyword(s):

T Cells ◽

Transcription Factor ◽

T Cell ◽

Interleukin 4 ◽

T Helper ◽

Recent Thymic Emigrants ◽

Antibody Isotype ◽

Helper Type

Abstract After intrathymic development, T cells exit the thymus and join the peripheral T-cell pool. Such recent thymic emigrants (RTEs) undergo both phenotypic and functional maturation during the first 3 weeks they reside in the periphery. Using a well-controlled in vitro polarization scheme, we now show that CD4+ RTEs are defective in T-helper (Th) type 0 (Th0), Th1, Th17, and regulatory T-cell lineage commitment, with dampened cytokine production and transcription factor expression. In contrast, CD4+ RTES are biased toward the Th2 lineage both in vitro and in vivo, with more robust interleukin-4, interleukin-5, and interleukin-13 production than their mature naive counterparts. Coculture experiments demonstrate that mature naive T cells influence neighboring RTEs in their Th responses. In adoptive hosts, CD4+ RTEs drive production of the Th2-associated antibody isotype immunoglobulin G1 and mediate airway inflammatory disease. This bias in RTEs likely results from dampened negative regulation of the Th2 lineage by diminished levels of T-bet, a key Th1 transcription factor. CD4+ RTEs thus represent a transitional population with a distinct interpretation of, and response to, immunologic cues. These characteristics may be beneficial during the postthymic maturation period by leading to the avoidance of inappropriate immune responses, particularly in lymphopenic neonates and adults.

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Selective development of T helper (Th)2 cells induced by continuous administration of low dose soluble proteins to normal and beta(2)-microglobulin-deficient BALB/c mice.

Journal of Experimental Medicine ◽

10.1084/jem.183.2.485 ◽

1996 ◽

Vol 183 (2) ◽

pp. 485-497 ◽

Cited By ~ 139

Author(s):

J C Guery ◽

F Galbiati ◽

S Smiroldo ◽

L Adorini

Keyword(s):

T Cells ◽

T Cell ◽

Th2 Cells ◽

Soluble Antigen ◽

Pathogenic Microorganisms ◽

T Helper ◽

Continuous Administration ◽

Ifn Gamma ◽

Beta 2 Microglobulin

Continuous administration of soluble proteins, delivered over a 10-d period by a mini-osmotic pump implanted subcutaneously, induces a long-lasting inhibition of antigen-specific T cell proliferation in lymph node cells from BALB/c mice subsequently primed with antigen in adjuvant. The decreased T cell proliferative response is associated with a down-regulation of the T helper cell (Th)1 cytokines interleukin (IL)-2 and interferon (IFN)-gamma and with a strong increase in the secretion of the Th2 cytokines IL-4 and IL-5 by antigen specific CD4+ T cells. This is accompanied by predominant inhibition of antigen-specific antibody production of IgG2a and IgG2b, rather than IgG1 isotype. Interestingly, inhibition of Th1 and priming of Th2 cells is also induced in beta(2) microglobulin-deficient BALB/c mice, indicating that neither CD8+ nor CD4+ NK1.1+ T cells, respectively, are required. The polarization in Th2 cells is stably maintained by T cell lines, all composed of CD4+/CD8- cells expressing T cell receptor for antigen (TCR) alpha/beta chains, derived from BALB/c mice treated with continuous antigen administration, indicating that they originate from Th2 cells fully differentiated in vivo. This polarization is induced in BALB/c mice by continuous administration of any protein antigen tested, including soluble extracts from pathogenic microorganisms. Priming of Th2 cells is dose dependent and it is optimal for low rather than high doses of protein. Blocking endogenous IL-4 in vivo inhibits expansion of antigen-specific Th2 cells, but does not restore IFN-gamma production by T cells from mice treated with soluble antigen-specific Th2 cells, but does not restore IFN-gamma production by T cells from mice treated with soluble antigen, indicating the involvement of two independent mechanisms. Consistent with this, Th2 cell development, but not inhibition of Th1 cells, depends on non-major histocompatibility complex genetic predisposition, since the Th2 response is amplified in BALB/c as compared to DBA/2, C3H, or C57BL/6 mice whereas tested. These findings support the hypothesis that continuous release of low amounts of protein antigens from pathogenic microorganisms may polarize the immune response toward a Th2 phenotype in susceptible mouse strains.

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Altered Ligands Reveal Limited Plasticity in the T Cell Response to a Pathogenic Epitope

Journal of Experimental Medicine ◽

10.1084/jem.189.7.1111 ◽

1999 ◽

Vol 189 (7) ◽

pp. 1111-1120 ◽

Cited By ~ 31

Author(s):

Sabine Pingel ◽

Pascal Launois ◽

Deborah J. Fowell ◽

Christoph W. Turck ◽

Scott Southwood ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

Peptide Ligands ◽

Interleukin 4 ◽

Single Amino Acid ◽

Th2 Cells ◽

Th2 Response ◽

Altered Peptide Ligands

Experimental leishmaniasis offers a well characterized model of T helper type 1 cell (Th1)-mediated control of infection by an intracellular organism. Susceptible BALB/c mice aberrantly develop Th2 cells in response to infection and are unable to control parasite dissemination. The early CD4+ T cell response in these mice is oligoclonal and reflects the expansion of Vβ4/ Vα8-bearing T cells in response to a single epitope from the parasite Leishmania homologue of mammalian RACK1 (LACK) antigen. Interleukin 4 (IL-4) generated by these cells is believed to direct the subsequent Th2 response. We used T cells from T cell receptor–transgenic mice expressing such a Vβ4/Vα8 receptor to characterize altered peptide ligands with similar affinity for I-Ad. Such altered ligands failed to activate IL-4 production from transgenic LACK-specific T cells or following injection into BALB/c mice. Pretreatment of susceptible mice with altered peptide ligands substantially altered the course of subsequent infection. The ability to confer a healer phenotype on otherwise susceptible mice using altered peptides that differed by a single amino acid suggests limited diversity in the endogenous T cell repertoire recognizing this antigen.

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Alteration of Interleukin 4 Production Results in the Inhibition of T Helper Type 2 Cell–Dominated Inflammatory Bowel Disease in T Cell Receptor α Chain–Deficient Mice

Journal of Experimental Medicine ◽

10.1084/jem.190.5.607 ◽

1999 ◽

Vol 190 (5) ◽

pp. 607-616 ◽

Cited By ~ 75

Author(s):

Hideki Iijima ◽

Ichiro Takahashi ◽

Daisuke Kishi ◽

Jin-Kyung Kim ◽

Sunao Kawano ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Bowel Disease ◽

Cell Receptor ◽

Interleukin 4 ◽

T Helper ◽

Inflammatory Bowel ◽

Α Chain

T cell receptor α chain–deficient (TCR-α−/−) mice are known to spontaneously develop inflammatory bowel disease (IBD). The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4+TCR-ββ (CD4+ββ) T cells producing predominantly interleukin (IL)-4. To investigate the role of these Th2-type CD4+ββ T cells, we treated TCR-α−/− mice with anti–IL-4 monoclonal antibody (mAb). Approximately 60% of TCR-α−/− mice, including those treated with mock Ab and those left untreated, spontaneously developed IBD. However, anti–IL-4 mAb–treated mice exhibited no clinical or histological signs of IBD, and their levels of mucosal and systemic Ab responses were lower than those of mock Ab–treated mice. Although TCR-α−/− mice treated with either specific or mock Ab developed CD4+ββ T cells, only those treated with anti–IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon γ–specific expression. These findings suggest that IL-4–producing Th2-type CD4+ββ T cells play a major immunopathological role in the induction of IBD in TCR-α−/− mice, a role that anti–IL-4 mAb inhibits by causing Th2-type CD4+ββ T cells to shift to the Th1 type.

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Rapid Development of Th2 Activity During T Cell Priming

Clinical and Developmental Immunology ◽

10.1080/10446670310001598537 ◽

2003 ◽

Vol 10 (1) ◽

pp. 1-6 ◽

Cited By ~ 2

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.

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Potential Antiinflammatory Role of Insulin via the Preferential Polarization of Effector T Cells toward a T Helper 2 Phenotype

Endocrinology ◽

10.1210/en.2006-0686 ◽

2007 ◽

Vol 148 (1) ◽

pp. 346-353 ◽

Cited By ~ 95

Author(s):

Alexander Viardot ◽

Shane T. Grey ◽

Fabienne Mackay ◽

Donald Chisholm

Keyword(s):

T Cells ◽

Cell Differentiation ◽

T Cell ◽

Insulin Receptor ◽

T Cell Differentiation ◽

Receptor Expression ◽

T Helper ◽

Type Response ◽

Helper Type

Hyperglycemia in critical illness is a common complication and a strong independent risk factor for morbidity and death. Intensive insulin therapy decreases this risk by up to 50%. It is unclear to what extent this benefit is due to reversal of glucotoxicity or to a direct effect of insulin, because antiinflammatory effects of insulin have already been described, but the underlying mechanisms are still poorly understood. The insulin receptor is expressed on resting neutrophils, monocytes, and B cells, but is not detectable on T cells. However, significant up-regulation of insulin receptor expression is observed on activated T cells, which suggests an important role during T cell activation. Exogenous insulin in vitro induced a shift in T cell differentiation toward a T helper type 2 (Th2)-type response, decreasing the T helper type 1 to Th2 ratio by 36%. This result correlated with a corresponding change in cytokine secretion, with the interferon-γ to IL-4 ratio being decreased by 33%. These changes were associated with increased Th2-promoting ERK phosphorylation in the presence of insulin. Thus, we demonstrate for the first time that insulin treatment influences T cell differentiation promoting a shift toward a Th2-type response. This effect of insulin in changing T cell polarization may contribute to its antiinflammatory role not only in sepsis, but also in chronic inflammation associated with obesity and type 2 diabetes.

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Abstract 001: Axl Expression by CD4+ T Lymphocytes Promotes Salt-Dependent Hypertension

Hypertension ◽

10.1161/hyp.64.suppl_1.001 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Kristine M Wadosky ◽

Sri N Batchu ◽

Angie Hughson ◽

Kathy Donlon ◽

Craig N Morrell ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Cd4 T Cells ◽

White Blood Cells ◽

Interleukin 4 ◽

Th2 Cells ◽

Salt Hypertension ◽

Ifn Γ

Introduction: Our laboratory has shown that Axl, a receptor tyrosine kinase, is important in both vascular and immune functions during deoxycorticosterone acetate (DOCA)-salt hypertension. We hypothesized that Axl activity specifically in T lymphocytes could explain the dependence of hypertension on Axl. Methods and Results: We did adoptive transfers of either Axl+/+ or Axl-/- CD4+ T cells to RAG1-/- mice that lack mature T cells. Once CD4+ T cell repopulations were confirmed, we induced DOCA-salt hypertension for 6 weeks. Systolic blood pressure (BP, mmHg) increased by 20±5 in Axl+/+RAG-/- mice after DOCA-salt, but Axl-/- RAG-/- mice had increases in BP by only 6+3 after 6 weeks of DOCA-salt. We isolated naïve CD4+ T cells from both Axl+/+ and Axl-/- littermates and primed them under either Th1 or Th2 polarizing conditions in culture. Production of interferon gamma (IFN-γ ng/mL) was significantly decreased (-23%, p<0.05) in Axl-/- (396±23) compared to Axl+/+ (512±42) under Th1-priming. However, Axl had no effect on interleukin 4 (IL-4, ng/mL) production under Th2 polarizing conditions. Intracellular staining of the Th1/Th2 cells with IFN-γ and IL-4 antibodies by flow cytometry confirmed expression of cytokines in culture media. Complete blood counts showed that Axl-/- mice had significantly lower white blood cells due to decreased numbers of lymphocytes (4.5±0.7x10 9 ) compared to Axl+/+ mice (7.8±0.7x10 9 ). We found a higher population of AnnexinV (marker of early apoptosis)-positive peripheral leukocytes in Axl-/- mice (10±1%) compared to Axl+/+ (4±1%) by flow cytometry; while the percentages of dead cells (~10%) were similar between Axl+/+ and Axl-/- mice. Conclusions: Altogether we show that expression of Axl by T cells drives salt-induced hypertension. The mechanism of Axl-dependent effects on T cells occurs via T-cell-dependent expression of the pro-inflammatory cytokine IFN-γ. In addition, Axl plays a role in inhibiting lymphocyte apoptosis in the circulation. Future work will focus on how Axl expression in T cells affects T cell-dependent vascular remodeling during hypertension.

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A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells.

Journal of Experimental Medicine ◽

10.1084/jem.183.6.2669 ◽

1996 ◽

Vol 183 (6) ◽

pp. 2669-2674 ◽

Cited By ~ 654

Author(s):

F Powrie ◽

J Carlino ◽

M W Leach ◽

S Mauze ◽

R L Coffman

Keyword(s):

T Cells ◽

Growth Factor ◽

Cd4 T Cells ◽

Transforming Growth Factor ◽

Th2 Cells ◽

Tgf Beta ◽

T Helper ◽

Cd4 Cells ◽

Helper Type

A T helper type 1 (Th1)-mediated colitis with similarities to inflammatory bowel disease in humans developed in severe combined immunodeficiency mice reconstituted with CD45RB(high) CD4+ splenic T cells and could be prevented by cotransfer of CD45RB(low) CD4+ T cells. Inhibition of this Th1 response by the CD45RB(low) T cell population could be reversed in vivo by an anti-transforming growth factor (TGF) beta antibody. Interleukin (IL) 4 was not required for either the differentiation of function of protective cells as CD45RB(low) CD4+ cells from IL-4-deficient mice were fully effective. These results identify a subpopulation of peripheral CD4+ cells and TGF-beta as critical components of the natural immune regulatory mechanism, which prevents the development of pathogenic Th1 responses in the gut, and suggests that this immunoregulatory population is distinct from Th2 cells.

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