Requirement for a Complex Array of Costimulators in the Negative Selection of Autoreactive Thymocytes In Vivo

Li, Ruixia; Page, Dawne M.

doi:10.4049/jimmunol.166.10.6050

Cited by 41 publications

(36 citation statements)

References 55 publications

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“…To demonstrate that the few transferred MHC molecules could participate in negative selection of T cells, we set up bone marrow chimeras, in which the epithelial-derived MHC would be inefficiently used by DC. We took advantage of the requirement for the CD40 costimulatory molecule in the efficient deletion of Vb5 and Vb6 thymocytes by superantigens [28][29][30]. We therefore compared the extent of negative selection in either MHC II-deficient BM or CD40/MHC II double-deficient BM into B6, AKR or CBA recipients.…”

Section: Discussionmentioning

confidence: 99%

Intercellular MHC transfer between thymic epithelial and dendritic cells

2008

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Thymic dendritic cells (DC) and epithelial cells play a major role in central tolerance but their respective roles are still controversial. Epithelial cells have the unique ability to ectopically express peripheral tissue-restricted antigens conferring self-tolerance to tissues. Paradoxically, while negative selection seems to occur for some of these antigens, epithelial cells, contrary to DC, are poor negative selectors. Using a thymic epithelial cell line, we show the functional intercellular transfer of membrane material, including MHC molecules, occurring between epithelial cells. Using somatic and bone marrow chimeras, we show that this transfer occurs efficiently in vivo between epithelial cells and, in a polarized fashion, from epithelial to DC. This novel mode of transfer of MHC-associated, epithelial cell-derived self-antigens onto DC might participate to the process of negative selection in the thymic medulla.

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Section: Discussionmentioning

confidence: 99%

Intercellular MHC transfer between thymic epithelial and dendritic cells

2008

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“…Negative selection of double-positive thymocytes was significantly reduced in response to either Ag or anti-TCR/CD3 Ab in CD28-deficient mice (8). CD28 is also involved in thymocyte negative selection mediated by superantigen both in vitro (9, 10) and in vivo (11). Furthermore, it has been recently reported that prenatal blockade of B7-1 and B7-2 substantially inhibits clonal deletion of T cells in the thymus and leads to an accumulation of autoreactive T cells in the periphery (12).…”

Section: Cd28 Signal Enhances Apoptosis Of Cd8 T Cells After Strong Tmentioning

confidence: 99%

CD28 Signal Enhances Apoptosis of CD8 T Cells After Strong TCR Ligation

Martin

Anasetti

2003

The Journal of Immunology

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High avidity ligation of the TCR induces negative selection in the thymus and can also induce apoptosis of peripheral T cells. Costimulation through CD28 enhances T cell activation and facilitates negative selection in the thymus, but the role of CD28 in peripheral T cell deletional tolerance has not been investigated. We used 2C CD28 wild-type and 2C CD28-deficient strains to assess the effects of CD28 and TCR avidity on peripheral T cell expansion and apoptosis. We compared the activation, division, expansion, and apoptosis of CD28+/+ and CD28−/− 2C cells in response to self-Ag (Kb), alloantigens with intermediate (Kbm3), high (Ld), or very high (Ld + QL9 peptide) avidity. With intermediate avidity alloantigen, the CD28 signal enhanced T cell activation and expansion. However, when T cells encountered high avidity alloantigen, the CD28 signal reduced T cell expansion and increased apoptosis. These results indicate that the CD28 signal can down-regulate peripheral T cell responses by increasing apoptosis when TCR ligation exceeds a critical threshold.

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“…7 D and E). The CD40-CD154 pathway is crucial for negative selection of autoreactive thymocytes (31,32). However, WT and CD154 Ϫ/Ϫ thymocytes undergo equivalent and efficient negative selection when they coexist in the thymus of mixed bone marrow chimeric mice, indicating that CD154 signaling is not required specifically on those cells undergoing negative selection (32).…”

Section: Cd154 Is Required Specifically In Developing Foxp3mentioning

confidence: 99%

Foxp3⁺regulatory T cells promiscuously accept thymic signals critical for their development

Spence

Green

2008

Proc. Natl. Acad. Sci. U.S.A.

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Foxp3 ؉ regulatory T cells develop in the thymus and are essential for maintaining peripheral tolerance to self tissues. We report the critical requirement for CD154 up-regulation specifically on, and during the thymic development of, Foxp3 ؉ regulatory T cells for the induction of their clonal expansion within the medulla. In the absence of this signal, there was a severe reduction in their thymic generation and output, leading to decreased peripheral numbers. Importantly, CD40 expression on either thymic dendritic or epithelial cells was sufficient to promote the development of normal numbers of Foxp3 ؉ regulatory T cells. This work suggests that CD154-transduced signals promote Foxp3 ؉ regulatory T cell development and highlights the plasticity of the thymic stroma for supporting their generation. Crucially, this study demonstrates that Foxp3 ؉ regulatory T cells can promiscuously accept a single critical signal necessary for their thymic development from different cellular sources, redefining our understanding of their generation.CD154 ͉ thymus ͉ thymic epithelial cells ͉ CD40 R egulatory T cells (Tregs) actively suppress autoreactive T cells, thereby limiting aberrant immune responses and maintaining tolerance toward self tissues (1). Deficiencies in this T cell subset in humans and mice can lead to severe autoimmunity. Initially, these suppressor cells were identified as CD4 ϩ CD25 ϩ T cells (2), a phenotype that also included activated CD4 ϩ T cells, but, recently, Foxp3 has been characterized as the master regulator of their development and function (3-5) and is used as a highly specific marker for Tregs (6). Foxp3 ϩ Tregs develop in the thymus as part of the normal T cell ontogeny processes (7), and Foxp3 expression is largely restricted to the thymic medulla and CD4 ϩ CD8 Ϫ (CD4SP) thymocyte subset; the end stage of CD4 ϩ T cell development. Thymic output of Foxp3 ϩ Tregs is temporally delayed (8), and their development requires a highaffinity self-reactive T cell receptor (9, 10), the costimulatory molecule CD28 (11), and possibly IL-2 (12). It has been suggested that medullary thymic epithelial cells (mTECs), which express and present tissue-specific antigens (TSAs) on MHC class II (MHC II) molecules, drive Foxp3 ϩ Treg selection (13). Similarly, dendritic cells (DCs) are thought to induce CD4 ϩ CD25 ϩ Tregs in the human thymus through a T cell antigen receptor (TCR)-peptide-MHC II interaction (14). However, the relative contributions of thymic dendritic and epithelial cells in promoting and supporting the development of a polyclonal Foxp3 ϩ Treg repertoire are not clear. In addition, the cellular origin and temporal importance of the signals necessary for Foxp3 ϩ Treg development have not been determined, and, therefore, the rules governing how developing Foxp3 ϩ Tregs receive and process these signals are poorly understood.We report that the CD40-CD154 pathway is critical for promoting the thymic development of Foxp3 ϩ Tregs. CD154 up-regulation specifically on developing Foxp3 ϩ Tregs promoted the...

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Requirement for a Complex Array of Costimulators in the Negative Selection of Autoreactive Thymocytes In Vivo

Cited by 41 publications

References 55 publications

Intercellular MHC transfer between thymic epithelial and dendritic cells

Intercellular MHC transfer between thymic epithelial and dendritic cells

CD28 Signal Enhances Apoptosis of CD8 T Cells After Strong TCR Ligation

Foxp3⁺regulatory T cells promiscuously accept thymic signals critical for their development

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Requirement for a Complex Array of Costimulators in the Negative Selection of Autoreactive Thymocytes In Vivo

Cited by 41 publications

References 55 publications

Intercellular MHC transfer between thymic epithelial and dendritic cells

Intercellular MHC transfer between thymic epithelial and dendritic cells

CD28 Signal Enhances Apoptosis of CD8 T Cells After Strong TCR Ligation

Foxp3+regulatory T cells promiscuously accept thymic signals critical for their development

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Foxp3⁺regulatory T cells promiscuously accept thymic signals critical for their development