Differential requirements of MHC and of DCs for endogenous proliferation of different T-cell subsets in vivo

Do, Jeong-Su; Min, Booki

doi:10.1073/pnas.0909954106

Cited by 29 publications

(48 citation statements)

References 31 publications

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“…We previously reported that naïve CD8 T-cell proliferation under lymphopenic conditions is not influenced by the lack of MHC I, and that the MHC I-independent CD8 proliferation requires MHC II (12). CD8 T cells that either are restricted to or crossrecognize MHC II have been reported previously (13,14), although the frequency of these cells is likely low.…”

Section: Resultsmentioning

confidence: 99%

“…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). This MHC I-independent proliferation is completely abolished in the absence of both MHC I and MHC II molecules, suggesting the possible involvement of a CD8 T-cell-MHC II molecule interaction in this proliferation (12).…”

mentioning

confidence: 99%

“…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). This MHC I-independent proliferation is completely abolished in the absence of both MHC I and MHC II molecules, suggesting the possible involvement of a CD8 T-cell-MHC II molecule interaction in this proliferation (12). Previous studies indicated that some CD8 T cells gain unusual reactivity to MHC II-restricted epitopes, especially in CD4-deficient hosts, after bacterial or viral infection (13,14).…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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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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“…Lymphopenia driven activation results from reduced competition for resources (MHC on dendritic cells and cytokines) that occurs within lymphopenic lymph nodes, and can be blocked by reducing lymph node stroma [5] or by increasing the number of competitor T cells [1]; polyclonal naïve T cells compete with each other to bind with self-MHC/peptide complexes and cytokines for their survival and homeostatic proliferation [36]. Therefore, we further tested our conclusion that PD-1 was needed to control homeostatic activation of RTE cells by using two separate approaches to increase the competition for resources.…”

Section: Control Of Lymphopenia Driven Activation and Autoimmunity Thmentioning

confidence: 99%

“…There is evidence for several distinct forms of LIP, including a rapid or acute proliferation (also called endogenous proliferation), a slower IL-7 dependent 'homeostatic' proliferation, and a rapid expansion of CD8 central memory cells that occurs in the presence of excess IL-15. Both the slow [2e4] and rapid [5] forms of LIP demonstrate dependence on the presence of adequate lymph node stroma, particularly in the case of CD4 LIP [2e4]. In contrast, the form of LIP that leads to proliferation of central memory CD8T cells, as occurs in lymphopenic mice lacking NK cells (e.g.…”

Section: Introductionmentioning

confidence: 98%

Programmed death-1 is required for systemic self-tolerance in newly generated T cells during the establishment of immune homeostasis

Thangavelu

Parkman

Ewen

et al. 2011

Journal of Autoimmunity

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Lymphopenia driven T cell activation is associated with autoimmunity. That lymphopenia does not always lead to autoimmunity suggests that control mechanisms may exist. We assessed the importance of the co-inhibitory receptor programmed death-1 (PD-1) in the control of lymphopenia-driven autoimmunity in newly generated T cells vs. established peripheral T cells and in thymic selection. PD-1 was not required for negative selection in the thymus or for maintenance of self tolerance following transfer of established PD-1⁻/⁻ peripheral T cells to a lymphopenic host. In contrast, PD-1 was essential for systemic self tolerance in newly generated T cells under lymphopenic conditions, as PD-1⁻/⁻ recent thymic emigrants (RTE), generated after transfer of PD-1⁻/⁻ hematopoietic stem cell (HSC) precursors or thymocytes into lymphopenic adult Rag⁻/⁻ recipients, induced a rapidly lethal multi-organ inflammatory disease. Disease could be blocked by using lymph node deficient recipients, indicating that lymphopenia driven PD-1⁻/⁻ T cell activation required access to sufficient lymph node stroma. These data suggested that PD-1⁻/⁻ mice themselves might be substantially protected from autoimmunity because their T cell repertoire is first generated early in life, a period naturally deficient in lymph node stroma. Consistent with this idea, neonatal Rag⁻/⁻ recipients of PD-1⁻/⁻ HSC were resistant to disease. Thus, a critical role of PD-1 resides in the control of RTE in lymphopenia. The data suggest that PD-1 and a paucity of lymphoid stroma cooperate to control autoimmunity in newly generated T cells. Clinical therapies for autoimmune disease employing lymphoablation and hematopoietic stem cell transplantation will need to take into account functional polymorphisms in the PD-1 pathway, if the treatment is to ameliorate rather than exacerbate autoimmunity.

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Lineage Targeted MHC-II Transgenic Mice Demonstrate the Role of Dendritic Cells in Bacterial-driven Colitis

Maggio‐Price

Seamons

Bielefeldt‐Ohmann

et al. 2013

Inflammatory Bowel Diseases

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Background Inflammatory bowel disease (IBD) pathogenesis involves an inadequately controlled immune reaction to intestinal microbiota and CD4+ T cells, dependent upon MHC class II (MHC-II) processing and presentation by antigen presenting cells (APC), play important roles The role of professional APC (macrophages and dendritic cells (DC)) and nonprofessional APC (intestinal epithelial cells (IEC)) in microbial driven intestinal inflammation remains controversial. Methods We generated transgenic animals on a MHC-II−/− genetic background in which MHC-II is expressed on a) DC via the CD11c promoter (CD11cTg) or b) IEC via the fatty acid binding protein (liver) promoter (EpithTg). These mice were crossed with Rag2−/− mice to eliminate T and B cells (CD11cTg/Rag2−/− and EpithTg/Rag2−/−). Helicobacter bilis (Hb) infection and adoptive transfer (AT) of naïve CD4+ T cells were used to trigger IBD. Results CD11cTg/Rag2−/− mice infected with Hb+AT developed severe colitis within three weeks post AT, similar to disease in positive control Rag2−/− mice infected with Hb+AT. CD11cTg/Rag2−/− mice given AT alone or Hb alone had significantly less severe colitis. In contrast, EpithTg/Rag2−/− mice infected with Hb+AT developed mild colitis by three weeks and even after 16 weeks post adoptive transfer, had only mild lesions. Conclusions MHC-II expression restricted to DCs is sufficient to induce severe colitis in the presence of T cells and a microorganism such as Hb within three weeks of adoptive transfer. Expression of MHC-II solely on IEC in the presence of a microbial trigger and T cells was insufficient for triggering severe colitis.

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Differential requirements of MHC and of DCs for endogenous proliferation of different T-cell subsets in vivo

Cited by 29 publications

References 31 publications

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

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

Programmed death-1 is required for systemic self-tolerance in newly generated T cells during the establishment of immune homeostasis

Lineage Targeted MHC-II Transgenic Mice Demonstrate the Role of Dendritic Cells in Bacterial-driven Colitis

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