MHC Class I-Positive Dendritic Cells (DC) Control CD8 T Cell Homeostasis In Vivo: T Cell Lymphopenia as a Prerequisite for DC-Mediated Homeostatic Proliferation of Naive CD8 T Cells

Gruber, Anton; Brocker, Thomas

doi:10.4049/jimmunol.175.1.201

Cited by 26 publications

(35 citation statements)

References 41 publications

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“…Conversely, constitutive ablation of cDCs through the expression of diphtheria toxin in CD11c + cells has been reported to cause fatal T-cell-mediated autoimmune disease (20) or a myeloid proliferative syndrome without obvious alterations of T-cell homeostasis (21). Mechanistically, peripheral DCs have been implicated in promoting homeostatic proliferation and survival of T cells (22)(23)(24) as well as inducing a low-level tonic signaling in naive T cells to program their responsiveness to foreign antigens (25). Moreover, although a direct role for DCs to promote T reg expansion and accumulation has been established by recent elegant studies (17,26), how this effect contributes to immune homeostasis is not fully understood (20,21,27,28).…”

mentioning

confidence: 99%

Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function

Wang¹,

Huang²,

Vogel³

et al. 2012

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

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Homeostatic control of dendritic cell (DC) survival is crucial for adaptive immunity, but the molecular mechanism is not well defined. Moreover, how DCs influence immune homeostasis under steady state remains unclear. Combining DC-specific and -inducible deletion systems, we report that transforming growth factor betaactivated kinase 1 (TAK1) is an essential regulator of DC survival and immune system homeostasis and function. Deficiency of TAK1 in CD11c + cells induced markedly elevated apoptosis, leading to the depletion of DC populations, especially the CD8 + and CD103 + DC subsets in lymphoid and nonlymphoid tissues, respectively. TAK1 also contributed to DC development by promoting the generation of DC precursors. Prosurvival signals from Toll-like receptors, CD40 and receptor activator of nuclear factor-κB (RANK) are integrated by TAK1 in DCs, which in turn mediated activation of downstream NF-κB and AKT-Foxo pathways and established a gene-expression program. TAK1 deficiency in DCs caused a myeloid proliferative disorder characterized by expansion of neutrophils and inflammatory monocytes, disrupted T-cell homeostasis, and prevented effective T-cell priming and generation of regulatory T cells. Moreover, TAK1 signaling in DCs was required to prevent myeloid proliferation even in the absence of lymphocytes, indicating a previously unappreciated regulatory mechanism of DC-mediated control of myeloid cell-dependent inflammation. Therefore, TAK1 orchestrates a prosurvival checkpoint in DCs that affects the homeostasis and function of the immune system. innate immunity | immune tolerance

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confidence: 99%

Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function

Wang¹,

Huang²,

Vogel³

et al. 2012

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

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“…Whether TCR-MHC interactions are necessary for maintaining cell survival in the periphery remains a matter of debate (1)(2)(3)(4)(5); however, these "low-affinity" interactions can promote antigen sensitivity of CD4 T cells, in part by sustaining partial TCR-ζ chain phosphorylation (6). Under lymphopenic settings, naïve T cells undergo endogenous proliferation (7,8) induced in part by recognition of self-peptide-MHC complexes, occurring in a MHC-restricted manner (9)(10)(11). Unlike naïve CD4 T cells that fail to proliferate in MHC II-deficient lymphopenic recipients, naïve CD8 T cells undergo substantial proliferation in MHC I-deficient lymphopenic conditions (12).…”

mentioning

confidence: 99%

Unexpected role for MHC II–peptide complexes in shaping CD8 T-cell expansion and differentiation in vivo

Valujskikh

Vignali

et al. 2012

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

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Here we report a unique role for MHC II-peptide complexes in controlling immune responses of naïve CD8 T cells. Compared with CD8 T cells from WT mice, CD8 T cells isolated from MHC II −/− mice hyperproliferated under lymphopenic conditions, differentiated into effector cells producing proinflammatory cytokines, and mediated more severe tissue inflammation. The elevated responses of MHC II −/− CD8 T cells were due to the absence of MHC II, but not CD4, T cells. The hyperreactivity appeared to be a feature of mature T cells, given its absence in CD8 single positive thymocytes derived from MHC II −/− mice. Expression of the MHC II ligand LAG3 was markedly enhanced during in vivo activation of MHC II −/− CD8 T cells, and blockade of MHC II-LAG3 interactions further enhanced T-cell expansion. Importantly, CD8 T cells isolated from H-2M −/− mice expressing WT levels of MHC II also displayed hyperresponsiveness similar to that of MHC II −/− CD8 T cells, suggesting that peptides presented on MHC II are involved in the control of CD8 T-cell responses. Our results uncover a previously undefined MHC II-dependent regulation that tunes CD8 T-cell reactivity and may have implications for an improved understanding of CD8 T-cell homeostasis and functions.lymphocytes | proliferation | lymphopenia | self-peptide | proliferation

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“…The inability of additional CD45KO CD11c + cells to rescue the reduced LIP in 45RAGKO mice indicated that the rescue was not simply due to an increase in DC number, but is due to a defect in CD45KO CD11c + cells that renders them unable to support spontaneous proliferation as efficiently as WT cells. It has been reported by multiple groups that DCs are required for or can enhance the LIP of T cells (28,29,38); however, it remains unclear exactly what signals are being provided by these cells other than the TCR signal provided by the MHC-peptide complex. We could not find a defect in the ability of CD45KO DCs to stimulate Ag-specific T cells to proliferate.…”

Section: Discussionmentioning

confidence: 99%

“…CD11c + DCs have been shown to promote CD8 LIP (28,29), but the subsets of DCs involved and the signals required are not known. It was found that 45RAGKO mice have slightly increased numbers and proportions of plasmacytoid DCs (CD11c int PDCA-1 + ), and a decreased proportion of CD11c hi MHC class II hi conventional DCs in the spleen (data not shown).…”

Section: Cd45ko Dcs Can Activate Ag-specific T Cells In Vitro and In mentioning

confidence: 99%

Innate Immune Cell CD45 Regulates Lymphopenia-Induced T Cell Proliferation

Saunders

Shim

Johnson

2014

The Journal of Immunology

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The leukocyte-specific tyrosine phosphatase, CD45, severely impacts T cell development and activation by modulating TCR signaling. CD45-deficient (CD45KO) mice have reduced peripheral T cell numbers where CD8 T cells are underrepresented. In this article, we show that CD45KO mice are unable to support efficient homeostatic proliferation, affecting CD8 T cells more than CD4 T cells. Using CD45-RAG1 double-deficient (45RAGKO) mice, we show that lymphopenia-induced proliferation (LIP) of CD45-sufficient T cells is defective in a host environment lacking CD45 on innate immune cells. We identify two deficiencies in the 45RAGKO mice that affect LIP. One involves CD11c+ cells and the second the production of IL-7 by lymphoid stromal cells. CD45KO dendritic cells were not defective in foreign Ag–induced T cell proliferation, yet CD45KO CD11c+ cells were unable to rescue the spontaneous LIP in the 45RAGKO mice. This was in contrast with the CD45-sufficient CD11c+ cells that partially rescued this spontaneous proliferation and did so without affecting IL-7 levels. The absence of CD45 also led to reduced IL-7 production by lymphoid stromal cells, suggesting an indirect effect of CD45 on innate immune cells in influencing IL-7 production by lymphoid stromal cells. These findings demonstrate a novel role for CD45 on innate immune cells in promoting lymphopenia-induced T cell proliferation and suggest that innate immune cells may communicate with stromal cells to regulate IL-7 production.

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MHC Class I-Positive Dendritic Cells (DC) Control CD8 T Cell Homeostasis In Vivo: T Cell Lymphopenia as a Prerequisite for DC-Mediated Homeostatic Proliferation of Naive CD8 T Cells

Cited by 26 publications

References 41 publications

Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function

Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function

Unexpected role for MHC II–peptide complexes in shaping CD8 T-cell expansion and differentiation in vivo

Innate Immune Cell CD45 Regulates Lymphopenia-Induced T Cell Proliferation

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