Cutting Edge: Antigen-Specific Thymocyte Feedback Regulates Homeostatic Thymic Conventional Dendritic Cell Maturation

Spidale, Nicholas A.; Wang, Bo; Tisch, Roland

doi:10.4049/jimmunol.1400321

Cited by 19 publications

(25 citation statements)

References 35 publications

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“…Thymic DC display a more activated phenotype relative to splenic DC (7). With this in mind, we tested if differences existed between thymic and splenic NOD DC to acquire MHC.…”

Section: Resultsmentioning

confidence: 99%

“…Thymic DC are broadly divided into three subsets: CD8α + conventional DC (cDC), signal regulatory protein α + (SIRPα + ) cDC, and plasmacytoid DC (pDC). Noteworthy is that thymic versus peripheral DC exhibit a more mature phenotype, suggesting distinct functional properties (7). Unlike mTEC, self-Ag must be acquired by thymic DC (8–10).…”

Section: Introductionmentioning

confidence: 99%

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Thymic Dendritic Cell Subsets Display Distinct Efficiencies and Mechanisms of Intercellular MHC Transfer

Kroger

Spidale

Wang

et al. 2017

The Journal of Immunology

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Thymic dendritic cells (DC) delete self-Ag-specific thymocytes, and drive development of FoxP3-expressing immunoregulatory T cells. Unlike medullary thymic epithelial cells (mTEC), which express and present peripheral self-Ag, DC must acquire self-Ag to mediate thymic negative selection. One such mechanism entails the transfer of surface MHC-self peptide complexes from mTEC to thymic DC. Despite the importance of thymic DC “cross-dressing” in negative selection, the factors that regulate the process, and the capacity of different thymic DC subsets to acquire MHC and stimulate thymocytes are poorly understood. Here intercellular MHC transfer by thymic DC subsets was studied using a MHC-mismatch-based in vitro system. Thymic conventional DC (cDC) subsets SIRPα+ and CD8α+ readily acquired MHC class I and II from TEC but plasmacytoid DC (pDC) were less efficient. Intercellular MHC transfer was donor cell-specific; thymic DC readily acquired MHC from TEC plus thymic or splenic DC, whereas thymic or splenic B cells were poor donors. Furthermore DC origin influenced cross-dressing; thymic versus splenic DC exhibited an increased capacity to capture TEC-derived MHC, which correlated with direct expression of EpCAM by DC. Despite similar capacities to acquire MHC-peptide complexes, thymic CD8α+ cDC elicited increased T cell stimulation relative to SIRPα+ cDC. DC cross-dressing was cell-contact dependent and unaffected by lipid raft disruption of donor TEC. Furthermore, blocking PI3K signaling reduced MHC acquisition by thymic CD8α+ cDC and pDC but not SIRPα+ cDC. These findings demonstrate that multiple parameters influence the efficiency of and distinct mechanisms drive intercellular MHC transfer by thymic DC subsets.

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“…Thymic DC display a more activated phenotype relative to splenic DC (7). With this in mind, we tested if differences existed between thymic and splenic NOD DC to acquire MHC.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thymic Dendritic Cell Subsets Display Distinct Efficiencies and Mechanisms of Intercellular MHC Transfer

Kroger

Spidale

Wang

et al. 2017

The Journal of Immunology

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“…It has in fact been demonstrated that CD40 plays an important role in the previously characterized cross-talk between thymic T cells and mTECs (19, 20). Moreover, a very recent study has reported the involvement of the CD40-CD40L pathway in cross-talk between thymic T cells and thymic DCs (48). The current finding of CD40 function on thymic B cells in mixed chimeras demonstrates a newly identified role of CD40 that is direct, and not the secondary consequence of CD40 effects on other populations, such as mTECs.…”

Section: Discussionmentioning

confidence: 99%

T Cell–B Cell Thymic Cross-Talk: Maintenance and Function of Thymic B Cells Requires Cognate CD40–CD40 Ligand Interaction

Fujihara

Williams

Watanabe

et al. 2014

The Journal of Immunology

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Thymic development requires bidirectional interaction or cross-talk between developing T cells and thymic stromal cells, a relationship that has been best characterized for the interaction between thymocytes and thymic epithelial cells (TECs). We have characterized here the requirement for similar cross-talk in the maintenance and function of thymic B cells, another population that plays a role in selection of developing thymic T cells. We found that maintenance of thymic B cells is strongly dependent upon the presence of mature single positive (SP) thymocytes and on the interactions of these T cells with specific antigen ligand. Maintenance of thymic B cell number is strongly dependent upon B cell-autonomous expression of CD40, but not MHCII, indicating that direct engagement of CD40 on thymic B cells is necessary to support their maintenance and proliferation. Thymic B cells can mediate negative selection of superantigen-specific self-reactive SP thymocytes, and we show that CD40 expression on B cells is critical for this negative selection. Cross-talk with thymic T cells is thus required to support the thymic B cell population through a pathway that requires cell-autonomous expression of CD40, and that reciprocally functions in negative selection of autoreactive T cells.

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“…18 These SP cells undergo apoptosis if they have a high or very low avidity when interacting with a TCR and the endogenous peptide coupled to major histocompatibility complex (MHC) class I or class II molecule expressed by microenvironmental cells in the thymus (particularly TECs and thymic dendritic cells [TDCs]). 17,19,20 In the medulla of the thymus, peripheral tissue antigens (PTAs) are expressed by TECs. 21 These PTAs are proteins or peptides specifically expressed in given tissues of the body that represent self-antigens of most paren chymal organs, such as insulin, which is expressed by the endocrine cells of pancreatic islets of Langerhans.…”

Section: T-cell Developmentmentioning

confidence: 99%

Hormonal control of T-cell development in health and disease

et al. 2015

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The physiology of the thymus, the primary lymphoid organ in which T cells are generated, is controlled by hormones. Data from animal models indicate that several peptide and nonpeptide hormones act pleiotropically within the thymus to modulate the proliferation, differentiation, migration and death by apoptosis of developing thymocytes. For example, growth hormone and prolactin can enhance thymocyte proliferation and migration, whereas glucocorticoids lead to the apoptosis of these developing cells. The thymus undergoes progressive age-dependent atrophy with a loss of cells being generated and exported, therefore, hormone-based therapies are being developed as an alternative strategy to rejuvenate the organ, as well as to augment thymocyte proliferation and the export of mature T cells to peripheral lymphoid organs. Some hormones (such as growth hormone and progonadoliberin-1) are also being used as therapeutic agents to treat immunodeficiency disorders associated with thymic atrophy, such as HIV infection. In this Review, we discuss the accumulating data that shows the thymus gland is under complex and multifaceted hormonal control that affects the process of T-cell development in health and disease.

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Cutting Edge: Antigen-Specific Thymocyte Feedback Regulates Homeostatic Thymic Conventional Dendritic Cell Maturation

Cited by 19 publications

References 35 publications

Thymic Dendritic Cell Subsets Display Distinct Efficiencies and Mechanisms of Intercellular MHC Transfer

Thymic Dendritic Cell Subsets Display Distinct Efficiencies and Mechanisms of Intercellular MHC Transfer

T Cell–B Cell Thymic Cross-Talk: Maintenance and Function of Thymic B Cells Requires Cognate CD40–CD40 Ligand Interaction

Hormonal control of T-cell development in health and disease

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