Intrathymic and extrathymic clonal deletion of T cells

Sprent, Jonathan; Webb, Susan R.

doi:10.1016/0952-7915(95)80004-2

Cited by 181 publications

(113 citation statements)

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“…DC are now implicated in the regulation of the responses they initiate and in the maintenance of tolerance to self components [1,2]. DC are involved in both central tolerance in the thymus [3,4] and in peripheral tolerance of self-reactive T cells that have escaped intra-thymic deletion [2,[5][6][7]. The activation or 'maturation' state of the DC is believed to determine the balance between tolerance and immunity.…”

Section: Introductionmentioning

confidence: 99%

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

et al. 2005

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Freshly isolated quiescent splenic dendritic cell (DC) subtypes differ in their capacity to activate naive CD4 T cells in culture. The CD8 + DC showed a reduced capacity to stimulate T cell proliferation compared to either of the CD8 -DC subsets, regardless of antigen and DC dose. In contrast to CD8 -DC, the quiescent CD8 + DC did not induce IFN-c production from CD4 T cells. The difference between the DC subtypes appeared to be at the level of initial surface molecule interactions, but could not be attributed to differences in expression of MHC class II or B7 family molecules, or to the expression of Fas ligand on DC. However, when activated by inclusion of the Toll-like receptor 9 ligand CpG in culture, CD8 + DC became potent stimulators of both CD4 T cell proliferation and IFN-c production. In contrast, similar activation of CD8 -DC produced a more modest increase in capacity to stimulate CD4 T cell proliferation and no increase in capacity to stimulate IFN-c production. The difference between a quiescent and an activated state is therefore more extreme for CD8 + than for CD8 -DC. The especially tight regulation of the activity of CD8 + DC may be essential for the maintenance of self tolerance.

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Section: Introductionmentioning

confidence: 99%

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

et al. 2005

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“…Positive selection allows TCR low CD4 ϩ CD8 ϩ immature thymocytes able to interact with self-peptide:self-MHC complexes to survive and differentiate into mature CD4 ϩ or CD8 ϩ single-positive TCR high thymocytes (3). Concomitantly, by inducing apoptosis, negative selection physically eliminates most thymocytes expressing TCRs with potentially harmful reactivity to self-peptide:self-MHC complexes (4,5). This intrathymic process is a major mechanism for the establishment of T cell tolerance.…”

mentioning

confidence: 99%

“…Intrathymic clonal deletion affects immature as well as semimature (CD4 ϩ CD8 Ϫ , HSA high ) thymocytes (7) and seems to require engagement of both TCR and costimulatory molecule receptors such as CD28 (5,8,9). The thymic medulla is rich in BM-derived cells expressing various costimulatory molecules and, therefore, is a very efficient site of negative selection.…”

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confidence: 99%

Functional and Phenotypic Evidence for Presentation of Eα52–68 Structurally Related Self-Peptide(s) in I-Eα-Deficient Mice

Viret

Janeway

2000

The Journal of Immunology

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The Y-Ae mAb and the 1H3.1 TCR-αβ (Vα1/Vβ6) are two immune receptors specific for I-Ab MHC class II molecules complexed to the 52–68 fragment of the α-chain of I-E class II molecules (the Eα52–68 peptide). A profound intrathymic negative selection occurs in 1H3.1 TCR transgenic mice in the presence of an I-Eα transgene. The administration of mAbs to 1H3.1/I-Eα double-transgenic newborn mice reveals that Y-Ae, but not the isotype-matched anti-I-E Y17 mAb, rescues a significant number of mature (Vβ6highCD4+CD8−) thymocytes and allows the detection of Eα52–68-reactive T cells in the periphery. These observations indicate that deletion of autoreactive T cells can be specifically inhibited in vivo by an mAb specific for the deleting self-peptide:self-MHC class II complex. Similar inhibition experiments indicate that C57BL/6 (I-Ab+/I-Eα−) mice constitutively express an Eα-independent, Y-Ae-recognizable epitope(s). This finding is confirmed by the phenotypic analysis of mature (MHC class II high) C57BL/6 bone marrow-derived dendritic cells. Collectively, these observations further illustrate the peptide specificity of negative selection and demonstrate that MHC class II-positive cells from unmanipulated C57BL/6 mice that lack a functional I-Eα gene can assemble one or more self-peptide:I-Ab complexes recognizable by the Eα52–68:I-Ab complex-specific Y-Ae mAb.

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“…This results in a strong expansion of antigen-specific lymphocytes within the LN [1]. The high number of antigen-responding CD4 T cells typically is not sustained, and only a small proportion of the cells persists [2,3]. Nevertheless, CD4 memory T cells can survive for long periods without continued contact with antigen [4][5][6], although it has been reported that such antigen-deprived cells may lack competence on reactivation in vivo [7].…”

Section: Introductionmentioning

confidence: 99%

Recirculating CD4 memory T cells mount rapid secondary responses without major contributions from follicular CD4 effectors and B cells

et al. 2007

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For weeks after primary immunization with thymus-dependent antigens the responding lymph nodes contain effector CD4 T cells in T zones and germinal centers as well as recirculating memory T cells. Conversely, remote nodes, not exposed to antigen, only receive recirculating memory cells. We assessed whether lymph nodes with follicular effector CD4 T cells in addition to recirculating memory CD4 T cells mount a more rapid secondary response than nodes that only contain recirculating memory cells. Also, the extent to which T cell frequency governs accelerated CD4 T cell recall responses was tested. For this, secondary antibody responses to a superantigen, where the frequency of responding T cells is not increased at the time of challenge, were compared with those to conventional protein antigens. With both types of antigens similar accelerated responses were elicited in the node draining the site of primary immunization and in the contralateral node, not previously exposed to antigen. Thus recirculating memory cells are fully capable of mounting accelerated secondary responses, without the assistance of CD4 effector T cells, and accelerated memory responses are not solely dependent on higher T cell frequencies. Accelerated memory CD4 T cell responses were also seen in B cell-deficient mice. IntroductionPrimary immunization with thymus-dependent antigens results in specific T and B cell responses in draining lymph nodes (LN). Naive CD4 T cells enter cell cycle after being primed by cognate interaction with dendritic cells in the T zones. This results in a strong expansion of antigen-specific lymphocytes within the LN [1]. The high number of antigen-responding CD4 T cells typically is not sustained, and only a small proportion of the cells persists [2,3]. Nevertheless, CD4 memory T cells can survive for long periods without continued contact with antigen [4][5][6], although it has been reported that such antigen-deprived cells may lack competence on reactivation in vivo [7].Antigen-experienced CD4 T cells have been classified into central memory and effector memory cells [8]. Central memory T cells have a slow turnover and express high levels of CCR7 and CD62L, which are both associated with homing to T zones of lymphoid tissues. Conversely, effector memory T cells home to inflamed tissues, have a rapid turnover, and are CCR7 -CD62L low . Both effector and central memory populations in vitro respond rapidly to low doses of antigen, but while LN draining the site of immunization develop substantial populations of antigen-specific CD4 effector T cells located in the follicles and outer T zone; these are not found in the remote LN. After immunization with limiting amounts of antigen, most antigen is trapped in the LN draining the site of immunization (draining LN) and lymphocyte activation is limited to this site. Several weeks after immunization draining LN will contain effector and memory CD4 T cells. In contrast, LN remote from the site of primary immunization (remote LN) will only have received recirculating memory ...

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Intrathymic and extrathymic clonal deletion of T cells

Cited by 181 publications

References 110 publications

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

Functional and Phenotypic Evidence for Presentation of Eα52–68 Structurally Related Self-Peptide(s) in I-Eα-Deficient Mice

Recirculating CD4 memory T cells mount rapid secondary responses without major contributions from follicular CD4 effectors and B cells

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