scholarly journals Early development of the T cell repertoire. In vivo treatment of neonatal mice with anti-Ia antibodies interferes with differentiation of I-restricted T cells but not K/D-restricted T cells.

1983 ◽  
Vol 157 (6) ◽  
pp. 1932-1946 ◽  
Author(s):  
A M Kruisbeek ◽  
M J Fultz ◽  
S O Sharrow ◽  
A Singer ◽  
J J Mond
Keyword(s):  
T Cells ◽  
Cell Function ◽  
Cytotoxic T Lymphocyte ◽  
Suppressor Cells ◽  
Accessory Cell ◽  
Cell Repertoire ◽  
Positive Elements ◽  
In Vivo Treatment ◽  
Ctl Responses

Monoclonal antibodies to I-Ak were injected into neonatal H-2k mice for a period of 3 wk. The spleens of such mice are devoid of Ia-positive cells. Allo- and trinitrophenyl (TNP)-self-specific cytotoxic T lymphocyte (CTL) responses in such anti-I-A-treated mice were almost completely abrogated at the end of the 2-3 wk in vivo treatment period. Development of suppressor cells, carry-over of blocking antibodies, lack of responder accessory cells, or defective CTL function were not responsible for the observed defect. As concanavalin A supernatant could restore the defect, it is more likely that the defect is due to the absence of competent Ia-specific T helper cells. In addition, anti-I-A-treated mice exhibit reduced I-A antigen expression in the thymus and defective Ia-bearing accessory cell function in the spleen. It is postulated that, for development of Ia-specific T cells to occur, precursor T cells need to interact with Ia-encoded products in the thymus, and anti-Ia treatment interferes with this process. Finally, the mechanism of this interference was shown to be due to actual removal or functional inactivation of those I-A-positive elements responsible for the education of I-A-recognizing T cells, since in (H-2b X H-2k)F1 mice, treatment with anti-I-Ak antibodies results in abrogation of CTL responses to TNP in association with both parental haplotypes, while in the thymus of these mice expression of both I-Ak and I-Ab was reduced.

scholarly journals CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

2009 ◽  
Vol 206 (2) ◽  
pp. 421-434 ◽  
Author(s):  
Randall H. Friedline ◽  
David S. Brown ◽  
Hai Nguyen ◽  
Hardy Kornfeld ◽  
JinHee Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Cytotoxic T Lymphocyte ◽  
Critical Role ◽  
Lymphoproliferative Disease ◽  
In Trans ◽  
And Function

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3+ regulatory T cells. CTLA-4–deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4–deficient and –sufficient bone marrow (BM)–derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4−/− T cells in trans by CTLA-4–sufficient T cells is a reversible process that requires the persistent presence of FOXP3+ regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3+ regulatory T cell function in vivo.

scholarly journals GENETIC CONTROL OF IMMUNE RESPONSES IN VITRO

1974 ◽  
Vol 140 (3) ◽  
pp. 648-659 ◽  
Author(s):  
Judith A. Kapp ◽  
Carl W. Pierce ◽  
Stuart Schlossman ◽  
Baruj Benacerraf
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Cell Function ◽  
Suppressor Cells ◽  
Specific Response ◽  
Spleen Cells ◽  
X Irradiation

In recent studies we have found that GAT not only fails to elicit a GAT-specific response in nonresponder mice but also specifically decreases the ability of nonresponder mice to develop a GAT-specific PFC response to a subsequent challenge with GAT bound to the immunogenic carrier, MBSA. Studies presented in this paper demonstrate that B cells from nonresponder, DBA/1 mice rendered unresponsive by GAT in vivo can respond in vitro to GAT-MBSA if exogenous, carrier-primed T cells are added to the cultures. The unresponsiveness was shown to be the result of impaired carrier-specific helper T-cell function in the spleen cells of GAT-primed mice. Spleen cells from GAT-primed mice specifically suppressed the GAT-specific PFC response of spleen cells from normal DBA/1 mice incubated with GAT-MBSA. This suppression was prevented by pretreatment of GAT-primed spleen cells with anti-θ serum plus C or X irradiation. Identification of the suppressor cells as T cells was confirmed by the demonstration that suppressor cells were confined to the fraction of the column-purified lymphocytes which contained θ-positive cells and a few non-Ig-bearing cells. The significance of these data to our understanding of Ir-gene regulation of the immune response is discussed.

scholarly journals CD8+ T Cells Mediate CD40-independent Maturation of Dendritic Cells In Vivo

1999 ◽  
Vol 189 (12) ◽  
pp. 1875-1884 ◽  
Author(s):  
Christiane Ruedl ◽  
Manfred Kopf ◽  
Martin F. Bachmann
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cd40 Ligand ◽  
Dc Maturation ◽  
Ctl Responses

Induction of cytotoxic T lymphocyte (CTL) responses against minor histocompatibility antigens is dependent upon the presence of T cell help and requires the interaction of CD40 on dendritic cells (DCs) with CD40 ligand on activated T helper cells (Th). This study demonstrates that CD40 is neither involved in Th-dependent nor Th-independent antiviral CTL responses. Moreover, the data show that DC maturation occurs in vivo after viral infection in the absence of CD40 and Th. This maturation did not require viral infection of  DCs but was mediated by peptide-specific CD8+ T cells. Surprisingly, naive CD8+ T cells were able to trigger DC maturation within 24 h after activation in vivo and in vitro. Moreover, peptide-activated CD8+ T cells were able to induce maturation in trans, as DCs that failed to present the relevant antigen in vivo also underwent maturation. Upon isolation, the in vivo–stimulated DCs were able to convert a classically Th-dependent CTL response (anti-HY) into a Th-independent response in vitro. Thus, antiviral CD8+ T cells are sufficient for the maturation of DCs in the absence of CD40.

scholarly journals Differential major histocompatibility complex-related activation of idiotypic suppressor T cells. Suppressor T cells cross-reactive to two distantly related lysozymes are not induced by one of them.

1980 ◽  
Vol 152 (3) ◽  
pp. 521-531 ◽  
Author(s):  
L Adorini ◽  
M A Harvey ◽  
D Rozycka-Jackson ◽  
A Miller ◽  
E E Sercarz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Cross Reactivity ◽  
Suppressor T Cells ◽  
Cell Repertoire ◽  
Helper Cells

B10 (H-2b) mice are genetic nonresponders to hen egg-white lysozyme (HEL) and the distantly related human lysozyme (HUL). However, anti-HEL or anti-HUL primary antibody responses in vivo or in vitro can be obtained in B10 mice by immunization with the appropriate lysozyme coupled to erythrocytes. T cells able to suppress either anti-lysozyme plaque-forming cells (PFC) response are induced in B10 mice after immunization with HEL-complete Freund's adjuvant (CFA) or HUL-CFA. This cross-reactivity of HEL and HUL in the induction and the expression of suppressive activity is in marked contrast to their very low cross-reactivity at the PFC level. These results suggest that either HEL or HUL can stimulate a suppressor T cell which recognizes a particular epitope present on both lysozymes. Suppressor cells induced by HEL or HUL bear the same predominant idiotype found on the majority of anti-HEL antibodies, and on the small proportion of anti-HUL antibodies cross-reactive with HEL. B10.Q (H-2q) mice are responders in vivo to HEL-CFA, but not to HUL-CFA. In contrast to B10, HEL-CFA priming in B10.Q micr induces helper cells whereas HUL-CFA priming induces suppressor cells. These suppressor cells are cross-reactive with HEL and are fully able to suppress HEL-specific helper cells. The presence of HEL-specific suppressor cell precursors in B10.Q mice which are not activated by HEL, seems to implicate differential choice by the antigen presenting system as a basis for Ir gene control, rather than the absence of a regulatory cell type from the T cell repertoire.

Stimulation of dendritic cells via the dectin-1/Syk pathway allows priming of cytotoxic T-cell responses

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4971-4980 ◽  
Author(s):  
Salomé LeibundGut-Landmann ◽  
Fabiola Osorio ◽  
Gordon D. Brown ◽  
Caetano Reis e Sousa
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cytotoxic T Cell ◽  
Immune Recognition ◽  
Cytotoxic T Cell Responses ◽  
Ctl Responses

Abstract The C-type lectin receptor dectin-1 functions as a pattern recognition receptor for β-glucans and signals via Syk kinase but independently of the Toll-like receptor (TLR) pathway to regulate expression of innate response genes. Dectin-1 signaling can promote activation of dendritic cells (DCs), rendering them competent to prime Th1 and Th17 responses. Here we show that dectin-1–activated DCs can also prime cytotoxic T-lymphocyte (CTL) responses. DCs exposed to a dectin-1 agonist induced antigen-specific expansion of TCR transgenic CD8+ T cells and their differentiation into CTLs in vitro. Dectin-1 agonist also acted as an adjuvant for CTL crosspriming in vivo, eliciting potent CTL responses that protected mice from tumor challenge. In vitro but not in vivo, CTL crosspriming was dependent on IL-12 p70, which was produced by dectin-1–activated DCs in response to IFN-γ secreted by newly activated CD8+ T cells. The dectin-1/Syk pathway is thus able to couple innate immune recognition of β-glucans to all branches of the adaptive immune system, including CD4+ T-helper cells, B cells, and CD8+ cytotoxic T cells. These data highlight the ability of non-TLR receptors to bridge innate and adaptive immunity and suggest that dectin-1 agonists may constitute useful adjuvants for immunotherapy and vaccination.

scholarly journals Reciprocal Changes in Tumor Antigenicity and Antigen-specific T Cell Function during Tumor Progression

2004 ◽  
Vol 200 (12) ◽  
pp. 1581-1592 ◽  
Author(s):  
Gang Zhou ◽  
Zhengbin Lu ◽  
John D. McCadden ◽  
Hyam I. Levitsky ◽  
Aimee L. Marson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Progression ◽  
Tumor Antigens ◽  
Cell Function ◽  
Early Recognition ◽  
Antigen Expression ◽  
Cell Repertoire ◽  
Antigen Loss

Two seemingly incompatible models exist to explain the progression of cancers in immunocompetent hosts. The cancer immunosurveillance hypothesis posits that recognition of transformed cells by the immune system results in the generation of an effector response that may impede tumor growth. Clinically detectable cancer results from the emergence of tumor variants that escape this selective pressure. Alternatively, induction of immune tolerance to tumor antigens may enable cancer progression. We established a model where changes in the function of tumor-specific T cells and in tumor antigen expression could be followed during cancer progression. Early recognition of antigen led to activation, expansion, and effector function in tumor-specific CD4+ T cells resulting in the outgrowth of tumors expressing substantially reduced levels of antigen. Antigen loss was not complete, however, and levels remained above the threshold required for tumor-specific T cell recognition in vivo. In the face of persisting antigen, T cell tolerance ensued, leading to an impaired ability to mediate further antigen loss. Together, these studies establish that the processes of immunosurveillance and tumor editing coexist with a process in which the functional tumor-specific T cell repertoire is also “edited,” reconciling two hypotheses historically central to our attempts to understand host antitumor immunity.

scholarly journals Bone marrow-generated dendritic cells pulsed with a class I-restricted peptide are potent inducers of cytotoxic T lymphocytes.

1995 ◽  
Vol 182 (1) ◽  
pp. 255-260 ◽  
Author(s):  
A Porgador ◽  
E Gilboa
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Cytotoxic T Lymphocyte ◽  
Lytic Activity ◽  
Class I ◽  
Effector Cells ◽  
Cd8 Cells ◽  
Ctl Responses

It has previously been shown that bone marrow-generated dendritic cells (DC) are potent stimulators in allogeneic mixed leukocyte reactions and are capable of activating naive CD4+ T cells in situ in an antigen-specific manner. In this study we have investigated whether bone marrow-generated DC are capable of inducing antigen-specific CD8+ T cell responses in vivo. Initial attempts to induce specific cytotoxic T lymphocyte (CTL) responses in mice injected with bone marrow-generated DC pulsed with ovalbumin (OVA) peptide were frustrated by the presence of high levels of nonspecific lytic activity, which obscured, though not completely, the presence of Ag-specific CTL. Using conditions that effectively differentiate between antigen-specific and nonspecific lytic activity, we have shown that bone marrow-generated DC pulsed with OVA peptide are potent inducers of OVA-specific CTL responses in vivo, compared with splenocytes or RMA-S cells pulsed with OVA peptide, or compared with immunization with free OVA peptide mixed with adjuvant. Antibody-mediated depletion experiments have shown that the cytotoxic effector cells consist primarily of CD8+ cells, and that induction of CTL in vivo is dependent on CD4+ as well as on CD8+ T cells. These results provide the basis for exploring the role of bone marrow-generated DC in major histocompatibility class I-restricted immune responses, and they provide the rationale for using bone marrow-generated DC in CTL-mediated immunotherapy of cancer and infectious diseases.

scholarly journals Nonmyeloablative Immunosuppressive Regimen Prolongs In Vivo Persistence of Gene-Modified Autologous T Cells in a Nonhuman Primate Model

2001 ◽  
Vol 75 (2) ◽  
pp. 799-808 ◽  
Author(s):  
Carolina Berger ◽  
Meei-Li Huang ◽  
Michael Gough ◽  
Philip D. Greenberg ◽  
Stanley R. Riddell ◽  
...  
Keyword(s):  
T Cells ◽  
Nonhuman Primate ◽  
Fluorescent Protein ◽  
Cytotoxic T Lymphocyte ◽  
Macaca Nemestrina ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Green Fluorescent ◽  
Ctl Responses

ABSTRACT The in vivo persistence of gene-modified cells can be limited by host immune responses to transgene-encoded proteins. In this study we evaluated in a nonhuman primate model whether the administration of a nonmyeloablative regimen consisting of low-dose total-body irradiation with 200 cGy followed by immunosuppression with mycophenolate mofetil and cyclosporin A for 28 and 35 days, respectively, could be used to facilitate persistence of autologous gene-modified T cells when a transgene-specific immune response had already been established or to induce long-lasting tolerance in unprimed recipients. Two macaques (Macaca nemestrina) received infusions of T cells transduced to express either the enhanced green fluorescent protein and neomycin phosphotransferase genes or the hygromycin phosphotransferase and herpes simplex virus thymidine kinase genes. In the absence of immunosuppression, both macaques developed potent class I major histocompatibility complex-restricted CD8+ cytotoxic T-lymphocyte (CTL) responses that rapidly eliminated the gene-modified T cells and that persisted long term as memory CTL. Treatment with the nonmyeloablative regimen failed to abrogate preexisting memory CTL responses but interfered with the induction of transgene-specific CTL and facilitated in vivo persistence of gene-modified cells in an unprimed host. However, sustained tolerance to gene-modified T cells was not achieved with this regimen, indicating that further modifications will be required to permit sustained persistence of gene-modified T cells.

scholarly journals Cd40-Independent Pathways of T Cell Help for Priming of Cd8+ Cytotoxic T Lymphocytes

2000 ◽  
Vol 191 (3) ◽  
pp. 541-550 ◽  
Author(s):  
Zhengbin Lu ◽  
Lingxian Yuan ◽  
Xianzheng Zhou ◽  
Eduardo Sotomayor ◽  
Hyam I. Levitsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cell Communication ◽  
Cd8 T Cell ◽  
Cd4 Help ◽  
T Cell Help

In many cases, induction of CD8+ CTL responses requires CD4+ T cell help. Recently, it has been shown that a dominant pathway of CD4+ help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4+ T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide–specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4+ T helper cells, respectively. We found that CD4+ T cells can provide potent help for DCs to activate CD8+ T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4+ help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4+–CD8+ T cell communication via lymphokines. Therefore, we conclude that CD4+ help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4+–CD8+ T cell communication.

Sign in / Sign up

Export Citation Format

Share Document