A central role for peripheral dendritic cells in the induction of acquired thymic tolerance

Goldschneider, Irving; Cone, Robert E.

doi:10.1016/s1471-4906(02)00038-8

Cited by 78 publications

(52 citation statements)

References 58 publications

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“…We also found that the percentage of DC among thymocytes remained constant after birth, i.e., the increase in numbers of thymic DC paralleled the increase in total number of thymocytes. These findings support the view that thymic DC play a role in thymocyte development, probably through involvement in the thymic negative selection processes (23)(24)(25)(26).…”

Section: Discussionsupporting

confidence: 87%

Development of the Dendritic Cell System during Mouse Ontogeny

Dakic

Shao

D’Amico

et al. 2004

The Journal of Immunology

123

139

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Based on the view that the efficacy of the immune system is associated with the maturation state of the immune cells, including dendritic cells (DC), we investigated the development and functional potential of conventional DC and plasmacytoid pre-DC (p-preDC) in spleen, thymus, and lymph nodes during mouse development. Both CD11c+ DC and CD45RA+ p-preDC were detected in small numbers in the thymus as early as embryonic day 17. The ratio of DC to thymocytes reached adult levels by 1 wk, although the normal CD8α+ phenotype was not acquired until later. Significant, but low, numbers of DC and p-preDC were present in the spleen of day 1 newborn mice. The full complement of DC and p-preDC was not acquired until 5 wk of age. The composition of DC populations in the spleen of young mice differed significantly from that found in adult mice, with a much higher percentage (50–60% compared with 20–25%) of the CD4−CD8α+ DC population and a much lower percentage (10–20% compared with 50–60%) of the CD4+CD8α− DC population. Although the p-preDC of young mice showed a capacity to produce IFN-α comparable with that of adult mice, the conventional DC of young mice were less efficient than those of their adult counterparts in IL-12p70 and IFN-γ production and in Ag presentation. These results suggest that the neonatal DC system is not fully developed, and innate immunity is the dominant form of response. The complete DC system required for adaptive immunity in the mouse is not fully developed until 5 wk of age.

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Section: Discussionsupporting

confidence: 87%

Development of the Dendritic Cell System during Mouse Ontogeny

Dakic

Shao

D’Amico

et al. 2004

The Journal of Immunology

123

139

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“…Chiffoleau et al (6) have provided yet another example of the ability of presumptive DCs to migrate to the thymus under tolerogenic conditions. In their experiments, donor origin MHCII ϩ APCs from a cardiac allograft were identified in the thymus of rats treated with the deoxyspergualine analog, LF15-0195, and were associated with the expansion of Ag-specific CD4 ϩ CD25 ϩ immunoregulatory thymocytes (48).…”

Section: Discussionmentioning

confidence: 99%

Two Developmentally Distinct Populations of Dendritic Cells Inhabit the Adult Mouse Thymus: Demonstration by Differential Importation of Hematogenous Precursors Under Steady State Conditions

Donskoy

Goldschneider

2003

The Journal of Immunology

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Although a variety of lymphoid and myeloid precursors can generate thymic dendritic cells (DCs) under defined experimental conditions, the developmental origin(s) of DCs in the steady state thymus is unknown. Having previously used selective combinations of normal, parabiotic, and radioablated mice to demonstrate that blood-borne prothymocytes are imported in a gated and competitive manner, we used a similar approach in this study to investigate the importation of the hematogenous precursors of thymic DCs. The results indicate that two developmentally distinct populations of DC precursors normally enter the adult mouse thymus. The first population is indistinguishable from prothymocytes according to the following criteria: 1) inefficient (<20%) exchange between parabiotic partners; 2) gated importation by the thymus; 3) competitive antagonism for intrathymic niches; 4) temporally linked generation of thymocytes and CD8αhigh DCs; and 5) absence from prothymocyte-poor blood samples. The second population differs diametrically from prothymocytes in each of these properties, and appears to enter the thymus in at least a partially differentiated state. The resulting population of DCs has a CD8α−/low phenotype, and constitutes ∼50% of total thymic DCs. The presence of two discrete populations of DCs in the steady state thymus implies functional heterogeneity consistent with evidence implicating lymphoid DCs in the negative selection of effector thymocytes and myeloid DCs in the positive selection of regulatory thymocytes.

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“…However, a role of peripheral dendritic cells in the modulation of acquired thymic tolerance has been documented before. 6,49 Taken together, BCR/ABL-expressing DCs do not efficiently induce specific CTL responses in secondary lymphoid organs but may present leukemia antigens in the thymus and induce central tolerance to these antigens. Both mechanisms may contribute to an impaired immunosurveillance of CML.…”

Section: Discussionmentioning

confidence: 99%

Defective homing and impaired induction of cytotoxic T cells by BCR/ABL-expressing dendritic cells

Mumprecht

Claus

Schürch

et al. 2009

Blood

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Chronic myelogenous leukemia (CML) is IntroductionChronic myelogenous leukemia (CML) is a malignant clonal myeloproliferative disease. The BCR/ABL fusion protein results from the reciprocal chromosomal translocation t(9;22) forming the Philadelphia chromosome (Ph). BCR/ABL is responsible for the malignant phenotype of leukemic cells in CML and increases cell proliferation, inhibits apoptotic processes, and alters cellular adhesion of myeloid cells. 1,2 CML is characterized by an initial chronic phase with a massive expansion of all stages of the granulocyte cell lineage. Eventually, hematopoietic differentiation becomes arrested and CML progresses to blast crisis with immature blast cells accumulating in the periphery. 1 Several studies have shown that cytotoxic T lymphocytes (CTLs) are involved in the immunosurveillance of CML. BCR/ ABL is a leukemia-specific antigen, and CTLs specific for peptides derived from its sequence could recognize CML cells in vitro and in vivo. 3,4 This suggests that there is efficient intracellular processing and presentation of BCR/ABL-derived peptides by CML cells. In addition, overexpressed self-proteins, such as proteinase-3, Wilms tumor 1 protein, and minor histocompatibility antigens, can act as leukemia-specific antigens for T cells. 5 Dendritic cells (DCs) are professional antigen-presenting cells and are key mediators for the initiation and regulation of both innate and adaptive immune responses. 6 DCs are a heterogeneous population that can be divided into myeloid and plasmacytoid DCs based on their origin, expression of surface markers, and function. 7 As CML mainly affects cells of the myeloid lineage, it is probable that myeloid BCR/ABL-expressing DCs are circulating in CML patients. Indeed, BCR/ABL-expressing DCs could be detected in the peripheral blood of CML patients. 7,8 However, CML patients in chronic phase had reduced numbers of circulating myeloid and plasmacytoid DCs compared with healthy persons. 9,10 Contradictory data regarding the maturation status and function of BCR/ABLexpressing DCs have been published. BCR/ABL-expressing DCs had either a normal maturation status or lower expression of the costimulatory molecules CD80/CD83/CD40 compared with control DCs. 7,8,11,12 In acute myeloid leukemia, the plasmacytoid DCs were immature and could not elicit the proliferation of naive CD4 ϩ T cells. 13 Moreover, in vitro-generated BCR/ABL-expressing DCs have been reported to be defective in antigen processing. 7,11 In contrast, other studies suggested that BCR/ABL-expressing DCs are able to effectively stimulate the proliferation of allogeneic and autologous T cells. 8,14 Similarly, vaccination with autologous, nonirradiated leukemic DCs induced antileukemic T-cell responses in some CML patients. 15 The function of BCR/ABL-expressing DCs in vivo is unknown. Therefore, we analyzed the function of BCR/ABL-expressing DCs in a murine retroviral-induced bone marrow transduction and transplantation model. 16 To study antigen-specific immune responses, we used H8 transgenic...

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A central role for peripheral dendritic cells in the induction of acquired thymic tolerance

Cited by 78 publications

References 58 publications

Development of the Dendritic Cell System during Mouse Ontogeny

Development of the Dendritic Cell System during Mouse Ontogeny

Two Developmentally Distinct Populations of Dendritic Cells Inhabit the Adult Mouse Thymus: Demonstration by Differential Importation of Hematogenous Precursors Under Steady State Conditions

Defective homing and impaired induction of cytotoxic T cells by BCR/ABL-expressing dendritic cells

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