CD25+ Immunoregulatory CD4 T Cells Mediate Acquired Central Transplantation Tolerance

Trani, Jose; Moore, Daniel J.; Jarrett, Beth P.; Markmann, Joseph W.; Lee, Major K.; Singer, Andrew L.; Lian, Moh-Moh; Tran, Brian; Caton, Andrew J.; Markmann, James F.

doi:10.4049/jimmunol.170.1.279

Cited by 40 publications

(28 citation statements)

References 44 publications

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“…In the CD4 ϩ CD8 Ϫ single-positive (CD4SP) subset, 6.5 ϩ CD25 Ϫ cells were also affected by negative selection as attested by a slight reduction in their frequency and a down-modulation of their transgenic TCR (Figure 2B), as previously noted in TCR-HA transgenic animals. 28,33 This reduction in 6.5 ϩ CD25 Ϫ cells in mice injected with the LvHA vector was accompanied by a striking enrichment of 6.5 ϩ CD25 ϩ cells compared with mice injected with a control vector (LvGFP) ( Figure 2B) or to noninjected mice (data not shown). In both LvGFP-and LvHA-injected mice, these 6.5 ϩ CD25 ϩ CD4SP thymocytes expressed high levels of the transcription factor foxp3, indicating that they have acquired a Treg phenotype ( Figure 2C).…”

Section: Resultsmentioning

confidence: 99%

Induction of antigen-specific tolerance by intrathymic injection of lentiviral vectors

Marodon

Fisson

Levacher

et al. 2006

Blood

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Immune tolerance to self-antigens is established during lymphocyte differentiation in the thymus, but a simple means to induce antigen-specific tolerance in the thymus is still elusive. We show here that intrathymic injection of a lentiviral vector expressing the hemagglutinin antigen (HA) in TCR IntroductionAt least 2 mechanisms are involved in the thymus to establish a self-tolerant although not self-ignorant immune system: negative selection of overtly self-reactive effector T cells and positive selection of a unique subset of self-reactive regulatory CD4 ϩ T cells (Tregs) expressing the ␣-chain of the interleukin-2 receptor (CD25) and the forkhead helix-winged transcription factor foxp3. 1 Injection in the thymus of organs, cells, peptide, or whole antigen, either under native or virally encoded forms, has been successful in the manipulation of T-cell-mediated immunologic tolerance. 2 Seminal findings were that allogeneic grafts of pancreatic islets had a better survival when grafted in the thymus, 3 and provided long-term protection against spontaneous autoimmune diabetes if grafted at birth. 4,5 Other investigators have used intrathymic delivery of adenoviral vectors to establish immune tolerance to viral antigens for ensuing gene therapy protocols. 6 It was later reported that intrathymic injection in neonates established longterm tolerance to adenoviral antigens with no need for prior lymphocyte depletion. 7 To induce T-cell-mediated tolerance, other investigators have relied on the expression of foreign MHC class I 8 or MHC class II alleles, 9 or preproinsulin, 10 on antigen-presenting cells after injection of autologous gene-modified hematopoietic stem cells. However, these studies did not formally demonstrate the involvement of the thymus in the tolerance process. The implication of the thymus has been documented in 2 recent studies related to the prevention of autoimmune responses following bone marrow transplantation. 11,12 In particular, it has been shown that thymic deletion of effector T cells correlated with diabetes protection in NOD mice reconstituted with gene-modified autologous hematopoietic stem cells (HSCs). 12 Besides negative selection (deletion) of overtly self-reactive T cells, a second major mechanism of central tolerance involves positive selection of CD4 ϩ CD25 ϩ foxp3 ϩ Tregs. The importance of Tregs for prevention of autoimmunity is perhaps best exemplified by the widespread autoimmune symptoms seen in patients deficient for FOXP3. 13 In the thymus, CD4 ϩ CD25 ϩ cells are detected during the fetal period in humans 14 and during the perinatal period in mice. 15,16 The regulatory function of Tregs is acquired during thymic selection, as shown by the ability of isolated CD4 ϩ CD25 ϩ thymocytes to suppress lymphocyte proliferation. 17 In most studies, expression of the nominal antigen in the thymus led to increased frequency and/or number of specific Tregs in T-cell receptor (TCR) transgenic mice, suggesting an "instructive" role for the antigen in Treg lineage commitment. [18][19][...

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Section: Resultsmentioning

confidence: 99%

Induction of antigen-specific tolerance by intrathymic injection of lentiviral vectors

Marodon

Fisson

Levacher

et al. 2006

Blood

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“…23 Intrathymic injection of donor-strain antigen results in a tolerant state, which was shown to be due to development of CD4 ϩ CD25 ϩ regulatory thymocytes. 24 Regulatory T cells with a CD4 ϩ CD25 ϩ phenotype are also known to be involved in experimental systems in which tolerance to alloantigens is induced in vivo with antibodies to T-cell surface antigens (eg, CD4, CD8, or CD154 23,[25][26][27][28][29] or with the active form of vitamin D 3 and mycophenolate mofetil. 30 In these systems, however, it is not clear if thymus-derived regulatory T cells (that can be found in naive animals) are involved or if these cells are induced in the periphery.…”

Section: Introductionmentioning

confidence: 99%

Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes

Joffre

Gorsse

Romagnoli

et al. 2004

Blood

154

115

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Thymus-derived regulatory T lymphocytes of CD4 ؉ CD25 ؉ phenotype regulate a large variety of beneficial and deleterious immune responses and can inhibit lethal graft-versus-host disease in rodents. In vitro, CD4 ؉ CD25 ؉ T cells require specific major histocompatibility complex (MHC)/peptide ligands for their activation, but once activated they act in an antigen-nonspecific manner. In vivo, regulatory T cells are also activated in an antigen-specific fashion, but nothing is known about antigen specificity of their suppressor-effector function. Here we show that CD4 ؉ CD25 ؉ regulatory T lymphocytes isolated from naive mice and activated in vitro with allogeneic antigenpresenting cells (APCs) induced specific long-term tolerance to bone marrow grafts disparate for major and minor histocompatibility antigens; whereas "target" bone marrow was protected, third-party bone marrow was rejected. Importantly, in mice injected with a mix of target and thirdparty bone marrows, protection and rejection processes took place simultaneously. These results indicate that CD4 ؉ CD25 ؉ regulatory T cells can act in an antigenspecific manner in vivo. Our results suggest that CD4 ؉ CD25 ؉ regulatory T cells could in the future be used in clinical settings to induce specific immunosuppression. ( IntroductionDue to the random rearrangements of genes encoding T-and B-lymphocyte antigen receptors, a significant number of autospecific and potentially autoreactive lymphocytes develop in primary lymphoid organs. [1][2][3] Central tolerance (ie, induced in primary lymphoid organs) eliminates (by deletion) or functionally inactivates (by induction of anergy) such dangerous lymphocytes. In absence of central tolerance induction, a strongly self-reactive T-cell repertoire develops. 4,5 However, when central tolerance is partially defective, self-tolerance can be maintained by peripheral mechanisms. [6][7][8] Several types of peripheral tolerance mechanisms control lymphocytes having escaped central tolerance and are known to play a crucial role in preventing autoimmunity (for reviews see Sprent et al 6 and Stockinger 9 ).One of these peripheral tolerance mechanisms was discovered using the day-3 thymectomy model of multiorgan autoimmunity in mice. 10 The pathology can be prevented by injection of CD4 ϩ CD25 ϩ lymphocytes, which appear after day 3 of life in the peripheral lymphoid organs of normal mice. CD4 ϩ CD25 ϩ regulatory T cells do not only inhibit autoimmunity, they can also inhibit experimental inflammatory bowel disease induced by injection of CD4 ϩ CD45RB high cells into severe combined immunodeficiency (SCID) mice or recombination-activating gene (RAG)-deficient animals. 11 Moreover, they contribute to the fine control of immunity to infectious agents such as parasites and viruses. 12,13 An undesired side effect of the activity of CD4 ϩ CD25 ϩ regulatory T lymphocytes is the occasional incapacity of the immune system to eliminate tumor cells. 14,15 Therefore, regulatory T lymphocytes play a crucial role in the pathophysiologic mai...

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“…TS1 and HA104 mice were bred internally and have been described for use in transplantation studies (15). Membrane IgM (mIgM) mice on a BALB/c background (16) were bred at Yale University School of Medicine under specific pathogen-free conditions.…”

Section: Micementioning

confidence: 99%

Cutting Edge: Transplant Tolerance Induced by Anti-CD45RB Requires B Lymphocytes

Deng

Moore

Huang

et al. 2007

The Journal of Immunology

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Selective interference with the CD45RB isoform by mAb (anti-CD45RB) reliably induces donor-specific tolerance. Although previous studies suggest participation of regulatory T cells, a mechanistic understanding of anti-CD45RB-induced tolerance is lacking. We report herein the unexpected finding that tolerance induced by this agent is not established in B cell-deficient mice but can be recovered by preemptive B lymphocyte transfer to B cell-deficient hosts. Using B cells from genetically modified donors to reconstitute B cell-deficient recipients, we evaluate the role of B lymphocyte-expressed CD45RB, T cell costimulatory molecules, and the production of Abs in this novel tolerance mechanism. Our data document an Ab-induced tolerance regimen that is uniquely B lymphocyte-dependent and suggest mechanistic contributions to tolerance development from the B cell compartment through interactions with T cells.

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CD25+ Immunoregulatory CD4 T Cells Mediate Acquired Central Transplantation Tolerance

Cited by 40 publications

References 44 publications

Induction of antigen-specific tolerance by intrathymic injection of lentiviral vectors

Induction of antigen-specific tolerance by intrathymic injection of lentiviral vectors

Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes

Cutting Edge: Transplant Tolerance Induced by Anti-CD45RB Requires B Lymphocytes

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