scholarly journals Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 628-636 ◽  
Author(s):  
Gang Zhou ◽  
Charles G. Drake ◽  
Hyam I. Levitsky
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Tumor Antigens ◽  
Suppressor Activity ◽  
Effector Cells ◽  
Immune Response To Cancer ◽  
Therapeutic Cancer Vaccines

AbstractThe fate of tumor-specific CD4+ T cells is central to the outcome of the host immune response to cancer. We show that tumor antigen recognition by a subset of CD4+ T cells led to their differentiation into cells capable of suppressing naive and Th1 effector cells. Such tumor-induced regulatory T cells (TMTregs) arose both from precommitted “natural” regulatory T cells and CD4+CD25–GITRlow precursors. Once induced, TMTregs were capable of maintaining suppressor activity long after transfer into antigen-free recipients. Suppression was mediated by GITRhigh cells residing within both CD25+ and CD25– subsets. Vaccination of the tumor-bearing host concomitantly expanded TMTregs and effector cells, but suppression was dominant, blunting the expansion of naive tumor-specific T cells and blocking the execution of effector function in vitro and in vivo. These studies illustrate the possibility that therapeutic vaccination could actually worsen host tolerance to tumor antigens and support treatment paradigms that seek to not only increase the frequency of tumor-specific T cells, but to do so in conjunction with strategies that inactivate or remove regulatory T-cell populations.

scholarly journals Leishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection.

1994 ◽  
Vol 179 (2) ◽  
pp. 447-456 ◽  
Author(s):  
S L Reiner ◽  
S Zheng ◽  
Z E Wang ◽  
L Stowring ◽  
R M Locksley
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Interleukin 12 ◽  
Insect Vector ◽  
T Helper 1 ◽  
Ifn Gamma ◽  
Effector Cells

Leishmania major are intramacrophage parasites whose eradication requires the induction of T helper 1 (Th1) effector cells capable of activating macrophages to a microbicidal state. Interleukin 12 (IL-12) has been recently identified as a macrophage-derived cytokine capable of mediating Th1 effector cell development, and of markedly enhancing interferon gamma (IFN-gamma) production by T cells and natural killer cells. Infection of macrophages in vitro by promastigotes of L. major caused no induction of IL-12 p40 transcripts, whereas stimulation using heat-killed Listeria or bacterial lipopolysaccharide induced readily detectable IL-12 mRNA. Using a competitor construct to quantitate a number of transcripts, a kinetic analysis of cytokine induction during the first few days of infection by L. major was performed. All strains of mice examined, including susceptible BALB/c and resistant C57BL/6, B10.D2, and C3H/HeN, had the appearance of a CD4+ population in the draining lymph nodes that contained transcripts for IL-2, IL-4, and IFN-gamma (and in some cases, IL-10) that peaked 4 d after infection. In resistant mice, the transcripts for IL-2, IL-4, and IL-10 were subsequently downregulated, whereas in susceptible BALB/c mice, these transcripts were only slightly decreased, and IL-4 continued to be reexpressed at high levels. IL-12 transcripts were first detected in vivo by 7 d after infection, consistent with induction by intracellular amastigotes. Challenge of macrophages in vitro confirmed that amastigotes, in contrast to promastigotes, induced IL-12 p40 mRNA. Reexamination of the cytokine mRNA at 4 d revealed expression of IL-13 in all strains analyzed, suggesting that IL-2 and IL-13 may mediate the IL-12-independent production of IFN-gamma during the first days after infection. Leishmania have evolved to avoid inducing IL-12 from host macrophages during transmission from the insect vector, and cause a striking induction of mRNAs for IL-2, IL-4, IL-10, and IL-13 in CD4+ T cells. Each of these activities may favor survival of the organism.

scholarly journals In Vivo Priming of Cd4 T Cells That Produce Interleukin (Il)-2 but Not IL-4 or Interferon (Ifn)-γ, and Can Subsequently Differentiate into IL-4–Or IFN-γ–Secreting Cells

2001 ◽  
Vol 194 (8) ◽  
pp. 1069-1080 ◽  
Author(s):  
Xiaowen Wang ◽  
Tim Mosmann
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Cell Receptor ◽  
Th2 Cells ◽  
Effector Cells ◽  
Ifn Γ

The differentiation of antigen-stimulated naive CD4 T cells into T helper (Th)1 or Th2 effector cells can be prevented in vitro by transforming growth factor (TGF)-β and anti–interferon (IFN)-γ. These cells proliferate and synthesize interleukin (IL)-2 but not IFN-γ or IL-4, and can differentiate into either Th1 or Th2 cells. We have now used two-color Elispots to reveal substantial numbers of primed cells producing IL-2 but not IL-4 or IFN-γ during the Th1- or Th2-biased immune responses induced by soluble proteins or with adjuvants. These cells were CD4+CD44high and were present during immediate and long-term immune responses of normal mice. Naive T cell receptor for antigen (TCR) transgenic (DO11.10) T cells were primed in vivo after adoptive transfer into normal hosts and FACS® cloned under conditions that did not allow further differentiation. After clonal proliferation, aliquots of each clone were cultured in Th1- or Th2-inducing conditions. Many in vivo–primed cells were uncommitted, secreting IL-2 but not IL-4 or IFN-γ at the first cloning step, but secreting either IL-4 or IFN-γ after differentiation in the appropriate conditions. These in vivo-primed, uncommitted, IL-2–producing cells may constitute an expanded pool of antigen-specific cells that provide extra flexibility for immune responses by differentiating into Th1 or Th2 phenotypes later during the same or subsequent immune responses.

scholarly journals Immunologic Self-Tolerance Maintained by Cd25+Cd4+Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4

2000 ◽  
Vol 192 (2) ◽  
pp. 303-310 ◽  
Author(s):  
Takeshi Takahashi ◽  
Tomoyuki Tagami ◽  
Sayuri Yamazaki ◽  
Toshimitsu Uede ◽  
Jun Shimizu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Lymphocyte ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Costimulatory Molecule ◽  
Self Tolerance

This report shows that cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) plays a key role in T cell–mediated dominant immunologic self-tolerance. In vivo blockade of CTLA-4 for a limited period in normal mice leads to spontaneous development of chronic organ-specific autoimmune diseases, which are immunopathologically similar to human counterparts. In normal naive mice, CTLA-4 is constitutively expressed on CD25+CD4+ T cells, which constitute 5–10% of peripheral CD4+ T cells. When the CD25+CD4+ T cells are stimulated via the T cell receptor in vitro, they potently suppress antigen-specific and polyclonal activation and proliferation of other T cells, including CTLA-4–deficient T cells, and blockade of CTLA-4 abrogates the suppression. CD28-deficient CD25+CD4+ T cells can also suppress normal T cells, indicating that CD28 is dispensable for activation of the regulatory T cells. Thus, the CD25+CD4+ regulatory T cell population engaged in dominant self-tolerance may require CTLA-4 but not CD28 as a costimulatory molecule for its functional activation. Furthermore, interference with this role of CTLA-4 suffices to elicit autoimmune disease in otherwise normal animals, presumably through affecting CD25+CD4+ T cell–mediated control of self-reactive T cells. This unique function of CTLA-4 could be exploited to potentiate T cell–mediated immunoregulation, and thereby to induce immunologic tolerance or to control autoimmunity.

scholarly journals Induced, but not natural, regulatory T cells retain phenotype and function following exposure to inflamed synovial fibroblasts

2020 ◽  
Vol 6 (44) ◽  
pp. eabb0606 ◽  
Author(s):  
Sujuan Yang ◽  
Ximei Zhang ◽  
Jingrong Chen ◽  
Junlong Dang ◽  
Rongzhen Liang ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Synovial Fibroblasts ◽  
Foxp3 Expression ◽  
Regulatory Function ◽  
Migration And Invasion ◽  
Effector Cells ◽  
T Effector Cells

Aberrant number and/or dysfunction of CD4+Foxp3+ Regulatory T cells (Tregs) are associated with the pathogenesis of rheumatoid arthritis (RA). A previous study has demonstrated that thymus-derived, natural Tregs (nTregs) prefer to accumulate in inflamed joints and transdifferentiate to TH17 cells under the stimulation of inflamed synovial fibroblasts (SFs). In this study, we made a head-to-head comparison of both Treg subsets and demonstrated that induced Tregs (iTregs), but not nTregs, retained Foxp3 expression and regulatory function on T effector cells (Teffs) after being primed with inflamed SFs. In addition, iTregs inhibited proliferation, inflammatory cytokine production, migration, and invasion ability of collagen-induced arthritis (CIA)–SFs in vitro and in vivo. Moreover, we noted that iTregs directly targeted inflamed SFs to treat autoimmune arthritis, while nTregs failed to do this. Thus, manipulation of the iTreg subset may have a greater potential for prevention or treatment of patients with RA.

scholarly journals Identification and In Vitro Expansion of Functional Antigen-Specific CD25+ FoxP3+ Regulatory T Cells in Hepatitis C Virus Infection

2008 ◽  
Vol 82 (10) ◽  
pp. 5043-5053 ◽  
Author(s):  
Hirotoshi Ebinuma ◽  
Nobuhiro Nakamoto ◽  
Yun Li ◽  
David A. Price ◽  
Emma Gostick ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Regulatory T Cells ◽  
Immune Regulation ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Foxp3 Expression

ABSTRACT CD4+CD25+ regulatory T cells (CD25+ Tregs) play a key role in immune regulation. Since hepatitis C virus (HCV) persists with increased circulating CD4+CD25+ T cells and virus-specific effector T-cell dysfunction, we asked if CD4+CD25+ T cells in HCV-infected individuals are similar to natural Tregs in uninfected individuals and if they include HCV-specific Tregs using the specific Treg marker FoxP3 at the single-cell level. We report that HCV-infected patients display increased circulating FoxP3+ Tregs that are phenotypically and functionally indistinguishable from FoxP3+ Tregs in uninfected subjects. Furthermore, HCV-specific FoxP3+ Tregs were detected in HCV-seropositive persons with antigen-specific expansion, major histocompatibility complex class II/peptide tetramer binding affinity, and preferential suppression of HCV-specific CD8 T cells. Transforming growth factor β contributed to antigen-specific Treg expansion in vitro, suggesting that it may contribute to antigen-specific Treg expansion in vivo. Interestingly, FoxP3 expression was also detected in influenza virus-specific CD4 T cells. In conclusion, functionally active and virus-specific FoxP3+ Tregs are induced in HCV infection, thus providing targeted immune regulation in vivo. Detection of FoxP3 expression in non-HCV-specific CD4 T cells suggests that immune regulation through antigen-specific Treg induction extends beyond HCV.

scholarly journals Suppressor activity and potency among regulatory T cells is discriminated by functionally active CD44

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 619-627 ◽  
Author(s):  
Mihail Firan ◽  
Sohita Dhillon ◽  
Pila Estess ◽  
Mark H. Siegelman
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Therapeutic Potential ◽  
Treg Cells ◽  
Peripheral Tolerance ◽  
In Vitro Proliferation ◽  
Suppressor Activity ◽  
Hyaluronan Binding

AbstractCD4CD25+ regulatory T cells are fundamental to the maintenance of peripheral tolerance and have great therapeutic potential. However, efforts in this regard have been hampered by limiting cell numbers in vivo, an anergic phenotype in vitro, and a rudimentary understanding of the molecular basis for the functional state of CD4CD25+ regulatory T cells (Treg cells). Here we show heterogeneity of suppressor activity among activated CD4CD25+ Treg cells and that, within this population, the functionally active, hyaluronan-binding form of CD44 (CD44act) is strikingly correlated with superior suppressor activity. Within 16 hours after in vitro activation, CD44act can discriminate enhanced suppressive function in in vitro proliferation assays and in an in vivo bone marrow engraftment model. The expression of other surface markers and that of Foxp3 are similar irrespective of hyaluronan binding and associated degree of suppressor potency. Furthermore, CD44act is induced on resting CD4CD25+ cells in vivo by allogeneic stimulation, with similar functional consequences. These results reveal a cell-surface marker that delineates functional activity within a population of activated CD4CD25+ regulatory T cells, thereby providing a potential tool for identifying regulatory activity and enriching for maximal suppressor potency.

Identification of a novel natural regulatory CD8 T-cell subset and analysis of its mechanism of regulation

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3294-3301 ◽  
Author(s):  
Emmanuel Xystrakis ◽  
Anne S. Dejean ◽  
Isabelle Bernard ◽  
Philippe Druet ◽  
Roland Liblau ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cell Subset ◽  
Interleukin 4 ◽  
Cell Contact

Abstract The immune system contains natural regulatory T cells that control the magnitude of the immune response during physiologic and pathologic conditions. Although this suppressive function was historically attributed to CD8 T cells, most recent reports have focused on natural regulatory CD4 T cells. In the present study, we describe a new subset of natural CD8 regulatory T cells in normal healthy animals. This subset expresses low levels of CD45RC at its surface (CD45RClow); produces mainly interleukin-4 (IL-4), IL-10, and IL-13 cytokines upon in vitro stimulation; expresses Foxp3 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4); and is not cytotoxic against allogeneic targets. This subset suppresses the proliferation and differentiation of autologous CD4 T cells into type-1 cytokines producing T cells after stimulation with allogeneic accessory cells. We also provide evidence that this regulatory subset mediates its suppression by cell-to-cell contact and not through secretion of suppressive cytokines. Finally, the regulatory activity of CD8 CD45RClow cells is also demonstrated in vivo in a rat model of CD4-dependent graft-versus-host disease. Collectively, these data demonstrate for the first time that freshly isolated rat CD8 CD45RClow T cells contain T cells with regulatory properties, a result that enlarges the general picture of T-cell-mediated regulation. (Blood. 2004;104:3294-3301)

Comparison of In Vitro and In Vivo Effects of Infliximab on Cytokine Production in Proliferating CD4+ T Cells in Patients with Rheumatoid Arthritis

2015 ◽  
Vol 1 (2) ◽  
pp. 122-128
Author(s):  
Syuichi Koarada ◽  
Yuri Sadanaga ◽  
Natsumi Nagao ◽  
Satoko Tashiro ◽  
Rie Suematsu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Cytokine Production

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.

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