Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells

Taams, Leonie S.; Vukmanovic‐Stejic, Milica; Smith, J. Maynard; Dunne, Pádraic J.; Fletcher, Jean M.; Plunkett, Fiona J.; Ebeling, Saskia B.; Lombardi, Giovanna; Rustin, M.H.A.; Bijlsma, J. W. J.; Lafeber, Floris P. J. G.; Salmon, Mike; Akbar, Arne N.

doi:10.1002/1521-4141(200206)32:6<1621::aid-immu1621>3.0.co;2-q

Cited by 226 publications

(198 citation statements)

References 35 publications

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“…The reduced downregulatory effect in patientderived CD4 + CD25 high T cells was detectable in the presence of unaltered CD4 + CD25 -T eff proliferation and concomitant IFN-c production, as previously described in several studies [8][9][10][11][12][13].…”

Section: Discussionsupporting

confidence: 77%

“…The murine counter- part of this T cell subset has an established role in the prevention of organ-specific autoimmune disease, including experimental allergic encephalomyelitis [5,26]. A similar subpopulation of CD4 + CD25 high T cells is present in human peripheral blood and lymphoid organs [6][7][8][9][10][11][12][13]. From a few recent studies, it appears that T reg numbers are reduced or their function is impaired in patients with various autoimmune disorders [17][18][19][20][21][22][23][24].…”

Section: Discussionmentioning

confidence: 99%

“…Within the human CD4 + subset only cells coexpressing high levels of CD25 appear to have potent regulatory function [6,7]. CD4 + CD25 high regulatory T cells (T reg ) are anergic to antigenic stimulation and actively downregulate activation and expansion of conventional T lymphocytes in a cell-contact-dependent and cytokine-independent manner [5, [8][9][10][11][12][13]. Although the molecular interactions and signaling pathways that are critical for their generation and function are nut fully elucidated, T reg require forkhead transcription factor scurfin encoded by the Foxp3 gene, which appears to control their development and regulatory properties [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, T reg can delay the onset and progression of autoimmune demyelination [26]. In this context it is interesting that also in humans, MOG is one of the most potent inducers of in vitro CD4 + T cell responses among various foreign and self antigens [7,13,27]. Importantly these responses could also be blocked by T reg from healthy individuals [27].…”

Section: Introductionmentioning

confidence: 99%

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Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

et al. 2005

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Immunoregulatory T cells of CD4 + CD25 + phenotype suppress T cell function and protect rodents from organ-specific autoimmune disease. The human counterpart of this subset of T cells expresses high levels of CD25 and its role in human autoimmune disorders is currently under intense investigation. In multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), the activation of circulating self-reactive T cells with specificity for myelin components is considered to be an important disease initiating event. Here, we investigated whether MS is associated with an altered ability of CD4 + CD25 high regulatory T cells (T reg ) to confer suppression of myelin-specific immune responses. Whereas T reg frequencies were equally distributed in blood and cerebrospinal fluid of MS patients and did not differ compared to healthy controls, the suppressive potency of patient-derived CD4 + CD25 high T lymphocytes was impaired. Their inhibitory effect on antigen-specific T cell proliferation induced by human recombinant myelin oligodendrocyte protein as well as on immune responses elicited by polyclonal and allogeneic stimuli was significantly reduced compared to healthy individuals. The effect was persistent and not due to responder cell resistance or altered survival of T reg , suggesting that a defective immunoregulation of peripheral T cells mediated by CD4 + CD25 high T lymphocytes promotes CNS autoimmunity in MS.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

et al. 2005

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“…4a). Collectively, these data demonstrated that Treg expanded in vitro with two or three cycles of xenoantigen-but not polyclonal-stimulation possessed the phenotypic characteristic of effector Treg, an important indicator for enhanced Treg function in immune suppression (Taams et al 2002;Dieckmann et al 2001;Baecher-Allan et al 2006). Furthermore, the increased level of Treg effector cytokine IL-10 gene expression by xenoantigen-stimulated Treg suggested that Xn-Treg may acquire potent suppressive activity in xenogeneic responses both in vitro and in vivo via IL-10-involved mechanisms (Sun et al 2010a, b;Yi et al 2012).…”

Section: High Numbers Of Human Treg Are Obtained After Expansion Withmentioning

confidence: 84%

Large-scale in vitro expansion of human regulatory T cells with potent xenoantigen-specific suppression

Jin

Lu²,

Zhao

et al. 2015

Cytotechnology

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Xenotransplantation is a potential solution to the organ donor shortage. Immunosuppression is required for successful application of xenotransplantation but may lead to infection and cancer. Thus, strategies for immune tolerance induction need to be developed. Polyclonal regulatory T cells (Treg) play a central role in the induction and maintenance of immune tolerance and have been shown to protect against islet xenograft rejection in vivo. However, global immune suppression may be mediated by polyclonal Treg immunotherapy and a simple method for in vitro expansion of xenoantigen-specific Treg for efficient Treg application becomes necessary. Human Treg isolated from peripheral blood mononuclear cells (PBMCs) were initially cultured with anti-CD3/CD28 beads, rapamycin and IL-2 for 7 days as polyclonal expansion. Expanded Treg were then cocultured with irradiated porcine PBMC as xenoantigen stimulation for three subsequent cycles with 7 days for each cycle in the presence of IL-2 and anti-CD3/CD28 beads. Treg phenotype and suppressive capacity were assessed after each cycle of xenoantigen stimulation. Treg expanded with one cycle of xenoantigen stimulation retained Treg suppressive phenotype but acquired no xenoantigen specificity along with poor expansion efficiency, whereas expansion with twocycle xenoantigen stimulation resulted in not only more than 800-fold Treg expansion but highly suppressive xenoantigen-specific Treg with effector Treg phenotype. However further increase of stimulation cycles resulted in reduced Treg suppressive potency. This study provides a simple approach to obtain high numbers of xenoantigen-specific Treg for immune tolerance induction in xenotransplantation.

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CD4+CD25+ regulatory T cells in rheumatoid arthritis: Differences in the presence, phenotype, and function between peripheral blood and synovial fluid

Amelsfort¹,

Jacobs²,

Bijlsma³

et al. 2004

Arthritis & Rheumatism

468

353

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Objective. In mice, CD4؉CD25؉ regulatory T cells play a pivotal role in preventing autoimmunity. Regulatory T cells are also present and functional in healthy humans. We investigated the presence, phenotype, and function of CD4؉CD25؉ regulatory T cells in peripheral blood (PB) and synovial fluid (SF) from patients with rheumatoid arthritis (RA).Methods. The presence and phenotype of CD4؉CD25؉ regulatory T cells were determined by flow cytometry. Anergy and suppressive activity were assessed by culturing CD4؉CD25؊ and CD4؉CD25؉ T cells with anti-CD3 monoclonal antibodies and antigen-presenting cells, followed by proliferation and cytokine detection.Results. The percentage of CD4؉CD25؉ T cells in RA SF was significantly increased compared with that in RA PB, and both of these percentages were higher than that in PB from controls. The cells in RA PB were similar in phenotype and function to CD4؉CD25؉ regulatory T cells from controls. In SF, however, ϳ40-50% of CD4؉CD25؉ T cells expressed an activated phenotype, i.e., CD69؉, class II MHC؉, OX-40؉, with high levels of CTLA-4 and glucocorticoid-induced tumor necrosis factor receptor. These synovial CD4؉CD25؉ T cells displayed an increased suppressive capacity compared with blood CD4؉CD25؉ T cells. However, this enhanced suppressive activity was counterbalanced, because activated responder T cells from SF were less susceptible to CD4؉CD25؉ T cell-mediated suppression than were responder cells from PB.Conclusion. We demonstrate that CD4؉CD25؉ regulatory T cells are present and functional in patients with RA, with higher numbers of regulatory T cells with increased suppressive activity found in SF compared with PB. These findings suggest a negative feedback system that is active at the site of inflammation. The balance between activated responder and regulatory T cells appears to influence the extent of immunoregulation in RA.

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Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells

Cited by 226 publications

References 35 publications

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

Large-scale in vitro expansion of human regulatory T cells with potent xenoantigen-specific suppression

CD4+CD25+ regulatory T cells in rheumatoid arthritis: Differences in the presence, phenotype, and function between peripheral blood and synovial fluid

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