scholarly journals The induction of cell-mediated immunity and tolerance with protein antigens coupled to syngeneic lymphoid cells.

1979 ◽  
Vol 149 (3) ◽  
pp. 758-773 ◽  
Author(s):  
S D Miller ◽  
R P Wetzig ◽  
H N Claman
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Lymphoid Cells ◽  
Delayed Hypersensitivity ◽  
Cell Mediated Immunity ◽  
Protein Antigens ◽  
Cyt C

A mouse model of cell-mediated immunity (CMI) and tolerance to protein antigens horse gamma globulin (HoGG) and cytochrome (Cyt C) was investigated. A reliable CMI response as measured in vivo by ear swelling or by an in vitro T-cell proliferation assay could be induced by one of two methods: (a) sensitization by antigen-complete Freund's adjuvant in the base of the tail, or (b) sensitization by s.c. injection of antigen coupled to syngeneic lymphoid cells. The in vivo response exhibited characteristic CMI parameters, delayed kinetics, and transfer by viable T cells. Prior i.v. injection of HoGG-modified lymphoid cells (HoGG-LC) or Cyt C-LC before sensitization resulted in a rapidly induced, dose-dependent, antigen-specific suppression of both in vivo and in vitro manifestations of the CMI response. In addition, tolerance in this system was transferrable by an antigen-specific suppressor T cell (Ts). The Ts were found to diminish the in vivo ear swelling reaction in recipient animals, but had no effect on the in vitro T-cell proliferative response of the recipients. In contrast to the rapid development of tolerance in donor mice (phenotypic tolerance), transferrable Ts were first demonstrable 4--7 d posttolerization. This latter result indicates that at least two mechanisms of tolerance are operative in this system: the rapid induction of clone inhibition of reactive T cells and the slower induction of Ts. These results indicate again that the mode of antigen presentation is crucial in determining the immunologic outcome. In these experiments, cell-bound proteins injected subcutaneously led to delayed hypersensitivity while the same antigens injected intravenously led to tolerance. These results are considered in the light of recent experiments which show that T cells recognize antigens on cells in association with major histocompatibility complex products. We believe the following pathways are involved. In sensitization via subcutaneous injection of HoGG-LC, antigen reaches the lymph node via lymphatic pathways which lead to immunogenic macrophage-associated presentation and the activation of delayed hypersensitivity T cells (TDH). In tolerization via intravenous injection of HoGG-LC, antigen (a) reaches the lymph node via the blood, probably directly meeting the TDH, preventing its subsequent activation by immunogenic HoGG (clone inhibition) and (b) reaches the spleen, also via the blood, activating suppressor T cells.

scholarly journals Migration ofAntigen-Specific T Cells Away from CXCR4-Binding Human ImmunodeficiencyVirus Type 1gp120

2004 ◽  
Vol 78 (10) ◽  
pp. 5184-5193 ◽  
Author(s):  
Diana M. Brainard ◽  
William G. Tharp ◽  
Elva Granado ◽  
Nicholas Miller ◽  
Alicja K. Trocha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Active Movement ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Cell Trafficking ◽  
Hiv 1

ABSTRACT Cell-mediated immunity depends in part on appropriate migration and localization of cytotoxic T lymphocytes (CTL), a process regulated by chemokines and adhesion molecules. Many viruses, including human immunodeficiency virus type 1 (HIV-1), encode chemotactically active proteins, suggesting that dysregulation of immune cell trafficking may be a strategy for immune evasion. HIV-1 gp120, a retroviral envelope protein, has been shown to act as a T-cell chemoattractant via binding to the chemokine receptor and HIV-1 coreceptor CXCR4. We have previously shown that T cells move away from the chemokine stromal cell-derived factor 1 (SDF-1) in a concentration-dependent and CXCR4 receptor-mediated manner. Here, we demonstrate that CXCR4-binding HIV-1 X4 gp120 causes the movement of T cells, including HIV-specific CTL, away from high concentrations of the viral protein. This migratory response is CD4 independent and inhibited by anti-CXCR4 antibodies and pertussis toxin. Additionally, the expression of X4 gp120 by target cells reduces CTL efficacy in an in vitro system designed to account for the effect of cell migration on the ability of CTL to kill their target cells. Recombinant X4 gp120 also significantly reduced antigen-specific T-cell infiltration at a site of antigen challenge in vivo. The repellant activity of HIV-1 gp120 on immune cells in vitro and in vivo was shown to be dependent on the V2 and V3 loops of HIV-1 gp120. These data suggest that the active movement of T cells away from CXCR4-binding HIV-1 gp120, which we previously termed fugetaxis, may provide a novel mechanism by which HIV-1 evades challenge by immune effector cells in vivo.

Cortisol increases CXCR4 expression but does not affect CD62L and CCR7 levels on specific T cell subsets in humans

2014 ◽  
Vol 306 (11) ◽  
pp. E1322-E1329 ◽  
Author(s):  
Luciana Besedovsky ◽  
Barbara Linz ◽  
Stoyan Dimitrov ◽  
Sabine Groch ◽  
Jan Born ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Cxcr4 Expression ◽  
T Cell Subsets ◽  
Lymph Node Homing ◽  
Endogenous Cortisol

Glucocorticoids are well known to affect T cell migration, leading to a redistribution of the cells from blood to the bone marrow, accompanied by a concurrent suppression of lymph node homing. Despite numerous studies in this context, with most of them employing synthetic glucocorticoids in nonphysiological doses, the mechanisms of this redistribution are not well understood. Here, we investigated in healthy men the impact of cortisol at physiological concentrations on the expression of different migration molecules on eight T cell subpopulations in vivo and in vitro. Hydrocortisone (cortisol, 22 mg) infused during nocturnal rest when endogenous cortisol levels are low, compared with placebo, differentially reduced numbers of T cell subsets, with naive CD4+ and CD8+ subsets exhibiting the strongest reduction. Hydrocortisone in vivo and in vitro increased CXCR4 expression, which presumably mediates the recruitment of T cells to the bone marrow. Expression of the lymph node homing receptor CD62L on total CD3+ and CD8+ T cells appeared reduced following hydrocortisone infusion. However, this was due to a selective extravasation of CD62L+ T cell subsets, as hydrocortisone affected neither CD62L expression on a subpopulation level nor CD62L expression in vitro. Corresponding results in the opposite direction were observed after blocking of endogenous cortisol synthesis by metyrapone. CCR7, another lymph node homing receptor, was also unaffected by hydrocortisone in vitro. Thus, cortisol seems to redirect T cells to the bone marrow by upregulating their CXCR4 expression, whereas its inhibiting effect on T cell homing to lymph nodes is apparently regulated independently of the expression of classical homing receptors.

scholarly journals Mimicry of the a determinant of hepatitis B surface antigen by an antiidiotypic antibody. I. Evaluation in hepatitis B surface antigen responder and nonresponder strains.

1993 ◽  
Vol 177 (1) ◽  
pp. 127-134 ◽  
Author(s):  
M W Pride ◽  
A Thakur ◽  
Y Thanavala
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Hepatitis B ◽  
Surface Antigen ◽  
Hepatitis B Surface Antigen ◽  
T Cell Response

B and T cell responses of several strains of mice, immunized with a monoclonal antiidiotype (anti-Id) that mimics the a determinant of hepatitis B surface antigen (HBsAg), were studied to determine if the immune response to the anti-Id was regulated by H-2-linked immune response genes as has been previously observed for HBsAg. We report that immunization with anti-Id could elicit HBsAg-specific antibodies in mice of the H-2d,q, or f haplotype and in an outbred wild mouse strain (Mus spretus), thus circumventing the H-2 haplotype restriction pattern observed when immunizing with HBsAg in H-2f mice. Purified lymph node T cells from mice of the H-2d or q haplotype and M. spretus that were primed in vivo with HBsAg or anti-Id could be stimulated in vitro with either HBsAg or anti-Id but not with an irrelevant antibody of the same subclass as the anti-Id. However, purified lymph node T cells from H-2f mice that were primed in vivo with the anti-Id could only be stimulated in vitro with anti-Id. No in vitro stimulation whatsoever was observed in H-2f mice immunized with HBsAg. The effect of processing and presentation of the anti-Id by antigen-presenting cells (APC) was studied in mice of the H-2d haplotype. Stimulation of purified lymph node T cells by HBsAg and anti-Id was shown to be strictly dependent on APC and restricted by major histocompatibility complex class II antigens at the I-A locus. Treatment of APC with paraformaldehyde or chloroquine abrogated the T cell response to all antigens except for a nine-amino acid synthetic peptide representing a partial analogue of the group a determinant of HBsAg S(139-147). The significance of these results is discussed in the context of understanding the mechanism of mimicry elicited by the anti-Id.

scholarly journals Studies on delayed hypersensitivity in mice. III. Evidence for suppressive regulatory T1-cell population in delayed hypersensitivity.

1977 ◽  
Vol 145 (2) ◽  
pp. 237-248 ◽  
Author(s):  
S Morikawa ◽  
M Baba ◽  
T Harada ◽  
A Mitsuoka
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Humoral Response ◽  
Delayed Hypersensitivity ◽  
Chemical Mediator ◽  
Surface Receptors ◽  
Foot Pad

T-T-cell interactions involved in delayed hypersensitivity (DH) response have been studied by employing delayed foot pad assay to methylated human serum albumin in C57BL/6J mice. The DH response, one of the T-cell manifestations of cell-mediated immune response is suppressively regulated by T cells and such observation was based on studies of age-associated kinetics of foot pad reaction and effects of cell transfer and adult thymectomy on developing DH response. These suppressively regulatory T cells in DH have a life span of less than 4 wk and a constant derivation from the thymus is required. Such cells are numerous in the young mouse thymus and few in the spleen and thymus of old mice. On the one hand, the presence of a long-lived effector T-cell population was suggested in DH. These cells are numerous in the spleen and are low responders to phytohemagglutinin in vitro. It is assumed that these suppressive T cells interact with antigen-reactive cells at their proliferating stage by recognition of the iodiotypic difference through surface receptors. As in the case of graft-vs.-host and humoral response in vivo, three different subsets of immune competent cells participate in the DH response. These cells consist of one specifically antigen-reactive T cell, one suppressive regulatory T cell, and one bone marrow-derived cell, a macrophage that responds to a chemical mediator from sensitized effector T cells and that develops a DH skin lesion nonspecifically.

scholarly journals Successful T cell priming in B cell-deficient mice.

1995 ◽  
Vol 182 (4) ◽  
pp. 915-922 ◽  
Author(s):  
M M Epstein ◽  
F Di Rosa ◽  
D Jankovic ◽  
A Sher ◽  
P Matzinger
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Protein Antigens ◽  
Capture Process ◽  
T Cell Priming ◽  
Deficient Mice

B cells are an abundant population of lymphocytes that can efficiently capture, process, and present antigen for recognition by activated or memory T cells. Controversial experiments and arguments exist, however, as to whether B cells are or should be involved in the priming of virgin T cells in vivo. Using B cell-deficient mice, we have studied the role of B cells as antigen-presenting cells in a wide variety of tests, including assays of T cell proliferation and cytokine production in responses to protein antigens, T cell killing to minor and major histocompatibility antigens, skin graft rejection, and the in vitro and in vivo responses to shistosome eggs. We found that B cells are not critical for either CD4 or CD8 T cell priming in any of these systems. This finding lends support to the notion that the priming of T cells is reserved for specialized cells such as dendritic cells and that antigen presentation by B cells serves distinct immunological functions.

scholarly journals L2C Guinea Pig Lymphatic Leukemia: A "B" Cell Leukemia

Blood ◽  
1972 ◽  
Vol 39 (1) ◽  
pp. 1-12 ◽  
Author(s):  
E. M. Shevach ◽  
L. Ellman ◽  
J. M. Davie ◽  
I. Green
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Guinea Pig ◽  
B Cell ◽  
B Lymphocyte ◽  
Lymphoid Cells ◽  
Cell Mediated Immunity ◽  
Lymphatic Leukemia

Abstract Lymphoid cells of the immune system can be divided into two functional compartments. The thymus derived population, "T" cells, is responsible for cell mediated immunity. The bone marrow derived population, "B" cells, is responsible for antibody production. Although these two populations are functionally different, it has not yet been possible to distinguish them morphologically. Recent experimental work in the mouse has shown that the B cells bear easily detectable immunoglobulin. The T cells can be distinguished by the isoantigen, theta. The B or T cell origin of the lymphocytes of human or animal leukemia has received little attention. In the present study, we have examined the functional and morphologic properties of a guinea pig lymphatic leukemia L2C. L2C cells secrete T2 immunoglobulin and also bear this immunoglobulin on their surface. L2C cells have the recently described lymphocyte receptor for antigen-antibody-complement complexes (found on normal B lymphocytes). Finally, the L2C cell fails to be stimulated in vitro by mitogens capable of stimulating thymus-derived lymphocytes. Thus, the L2C cell appears to be of B lymphocyte origin. The availability of a large number of pure B lymphoid cells will provide a useful tool for the study of the cellular receptors of lymphoid cells and for the preparation of antisera specific for the T cell and B cell populations. The application of the techniques described in this paper to classify other lymphoid neoplasms as to their T or B cell origin may lead to both theoretic and therapeutic advances.

scholarly journals Defective maintenance of T cell tolerance to a superantigen in MRL-lpr/lpr mice.

1992 ◽  
Vol 176 (4) ◽  
pp. 1063-1072 ◽  
Author(s):  
T Zhou ◽  
H Bluethmann ◽  
J Zhang ◽  
C K Edwards ◽  
J D Mountz
Keyword(s):  
Weight Loss ◽  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Lymph Nodes ◽  
Time Course ◽  
Cell Receptor ◽  
Peripheral Tolerance

In normal mice neonatal injection of staphylococcal enterotoxin B (SEB) induces tolerance in T cells that express reactive T cell receptor (TCR) V beta regions. To determine if a T cell neonatal defect was present in MRL-lpr/lpr mice, 20 micrograms of SEB was injected intraperitoneally every other day into V beta 8.2 TCR transgenic and nontransgenic MRL(-)+/+ and MRL-lpr/lpr mice from birth to 2 wk of age. At 2 wk of age, V beta 8+ T cells were depleted, and SEB reactivity was lost, in spleen, lymph node, and thymus. These effects were equivalent in +/+ and lpr/lpr SEB-tolerized mice. However, MRL-lpr/lpr mice failed to maintain neonatal tolerance. By 4 wk of age, there was a dramatic increase in T cells expressing V beta 8.2 in the peripheral lymph nodes of MRL-lpr/lpr mice but not MRL(-)+/+ mice. In vitro stimulation with SEB or TCR crosslinking revealed a total loss of neonatal tolerance 2 wk after cessation of SEB treatment in lpr/lpr mice, but not +/+ mice. The time-course of recovery of V beta 8+ T cells and reactivity to SEB and TCR crosslinking in the thymus of MRL-lpr/lpr mice was similar to that in the lymph node. Thymectomy at 2 wk of age eliminated tolerance loss in lymph nodes of MRL-lpr/lpr mice at 4 wk of age, indicating that loss of peripheral tolerance was due to the emigration of untolerized T cells from the thymus. Challenge of neonatally tolerized MRL-lpr/lpr mice with SEB (100 micrograms, i.p.) at 8 wk of age resulted in a dramatic onset of T cell-mediated autoimmune disease characterized by 30% weight loss and 60% morality. This indicated that loss of tolerance to SEB also occurred in vivo. In contrast, neonatally tolerized MRL(-)+/+ mice remained totally unresponsive to SEB challenge and did not undergo any detectable weight loss. These results suggest that there is normal induction of neonatal tolerance to SEB in lpr/lpr mice, but that tolerance is not maintained after the tolerizing antigen is removed. This loss of neonatal tolerance can lead to severe weight loss and death on exposure to the tolerizing antigen later in life.

scholarly journals Antigen-pulsed CD8α+ Dendritic Cells Generate an Immune Response after Subcutaneous Injection without Homing to the Draining Lymph Node

1999 ◽  
Vol 189 (3) ◽  
pp. 593-598 ◽  
Author(s):  
Adrian L. Smith ◽  
Barbara Fazekas de St. Groth
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Lymph Node ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Myeloid Dendritic Cells ◽  
Draining Lymph Node

Two subsets of murine splenic dendritic cells, derived from distinct precursors, can be distinguished by surface expression of CD8α homodimers. The functions of the two subsets remain controversial, although it has been suggested that the lymphoid-derived (CD8α+) subset induces tolerance, whereas the myeloid-derived (CD8α−) subset has been shown to prime naive T cells and to generate memory responses. To study their capacity to prime or tolerize naive CD4+ T cells in vivo, purified CD8α+ or CD8α− dendritic cells were injected subcutaneously into normal mice. In contrast to CD8α− dendritic cells, the CD8α+ fraction failed to traffic to the draining lymph node and did not generate responses to intravenous peptide. However, after in vitro pulsing with peptide, strong in vivo T cell responses to purified CD8α+ dendritic cells could be detected. Such responses may have been initiated via transfer of peptide–major histocompatibility complex complexes to migratory host CD8α− dendritic cells after injection. These data suggest that correlation of T helper cell type 1 (Th1) and Th2 priming with injection of CD8α+ and CD8α− dendritic cells, respectively, may not result from direct T cell activation by lymphoid versus myeloid dendritic cells, but rather from indirect modification of the response to immunogenic CD8α− dendritic cells by CD8α+ dendritic cells.

Rap1-GTP Promotes the Generation of Regulatory T Cells in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 110-110
Author(s):  
Lequn Li ◽  
Rebecca Greenwald ◽  
Esther M. Lafuente ◽  
Dimitrios Tzachanis ◽  
Alla Berezovskaya ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 Cells

Abstract Elucidating the mechanisms that regulate T cell activation and tolerance in vivo will provide insights into the maintenance of physiologic homeostasis and will facilitate development novel strategies for induction of transplantation tolerance. Transient activation of the small GTPase Rap1 is one of the physiologic consequences of TCR ligation and is mandatory for β1 and β2 integrin-mediated adhesion. In contrast, sustained increase of active Rap1 inhibits T cell activation and IL-2 transcription in vitro. In order to understand the role of Rap1 in the immune responses of the intact host we generated transgenic (Tg) mice, which express the active Rap1 mutant Rap1E63 in T cells. Rap1E63-Tg mice had no defects in thymocyte development or maturation. Rap1E63-Tg thymocytes were capable of activating Ras and Erk1/2 and, compared to wild type (WT) thymocytes, displayed enhanced LFA-1:ICAM-1-mediated adhesion and increased proliferation in response to anti-CD3. Surprisingly, although lymph node and splenic CD4+ cells from the Rap1E63-Tg mice also displayed increased LFA-1:ICAM-1-mediated adhesion, they had significantly impaired activation of Erk1/2 and dramatically reduced proliferation and IL-2 production in response to anti-CD3 and WT antigen presenting cells (APC). The defective responses of CD4+ T cells suggest that Rap1E63-Tg mice may have impaired helper function in vivo. To address this issue we immunized Rap1E63-Tg and WT mice with TNP-OVA, a T-cell dependent antigen. Total IgG, IgG1 and IgG2a were dramatically reduced, indicating that Rap1E63-Tg mice had a defect in immunoglobulin class switching, consistent with defective helper T cell-dependent B cell activation. Because these results suggest that Rap1E63-Tg CD4+ cells may have an anergic phenotype, we tested rechallenge responses. We immunized Rap1E63-Tg and WT mice with TNP-OVA in vivo and subsequently we rechallenged T cells in vitro with WT APC pulsed with OVA. Compared with WT, Rap1E63-Tg T cells had dramatically reduced proliferation, IFN- γ and IL-2 production on rechallenge, findings consistent with T cell anergy. Using suppression subtraction hybridization we determined that Rap1E63 induced mRNA expression of CD103, a marker that defines a potent subset of regulatory T cells (Treg). Strikingly, Rap1E63-Tg mice had a 5-fold increase of CD103+CD25+CD4+ Treg compared to WT mice. Rap1E63-Tg CD103+CD25+CD4+ Treg expressed the highest level of Foxp3 among all T cell subsets and had the most potent inhibitory effect on proliferation and IL-2 production when added into cultures of WT CD4+CD25− cells. Importantly, removal of the CD103+ cells significantly restored Erk1/2 activation, proliferation and IL-2 production of Rap1E63-Tg CD4+ T cells. Generation of CD103+ Treg occurs after thymic development and requires encounter of peripheral autoantigen. Consistent with this, differences in CD103+ Treg were detected only between lymph node and splenic cells and not between thymocytes from Rap1E63-Tg and WT mice. Since generation of CD103+ Treg depends on the strength of TCR signal, these results suggest that by enhancing adhesion, active Rap1 regulates the generation of Treg. Moreover, these results provide evidence that active Rap1 is a potent negative regulator of immune responses in vivo and have significant implications for the development of immune-based therapies geared towards tolerance induction.

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