T Cell TRAIL Promotes Murine Lupus by Sustaining Effector CD4 Th Cell Numbers and by Inhibiting CD8 CTL Activity

Rus, Violeta; Nguyen, Vinh; Puliaev, Roman; Puliaeva, Irina; Zernetkina, Valentina; Luzina, Irina G.; Papadimitriou, John C.; Via, Charles S.

doi:10.4049/jimmunol.178.6.3962

Cited by 36 publications

(36 citation statements)

References 63 publications

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“…Among our observations, a critical point is that helpless memory CD8 T cells exhibit a defect in granzyme B-mediated cytotoxic functions. In this respect, a recent observation suggested that TRAIL expression on CD8 T cells negatively regulates the granzymeB/perforin-mediated CD8 T cell killing (34). This suggests that heterospecific CD4 help to memory CD8 T cell may include a TRAIL-dependent component that could control not only survival but also cytotoxic functions.…”

Section: Discussionmentioning

confidence: 99%

Heterospecific CD4 Help to Rescue CD8 T Cell Killers

Herve

Cariou

Simonetta

et al. 2008

The Journal of Immunology

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Help from CD4 T cells may be required for optimal generation and maintenance of memory CD8 T cells and also for optimal Ag reactivation. We examined whether the helper cell and the CD8 killer cell need to have the same Ag specificity for help to be effective during interactions of memory T cells with mature APC. This is important because virus and tumor Ag-specific CD4 T cell responses are selectively impaired in several chronic viral infections and malignancies. We performed studies in vitro and in vivo and found that functional memory CD4 T cells generated from a distinct antigenic source (heterospecific helpers) could provide direct and effective help to memory CD8 T cells. Functional heterospecific memory CD4 T cells could also rescue secondary CD8 T cell responses in an experimental tumor model in which homospecific CD4 help was impaired. This could provide a rationale for immunotherapy strategies designed to bypass impaired homospecific help.

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Section: Discussionmentioning

confidence: 99%

Heterospecific CD4 Help to Rescue CD8 T Cell Killers

Herve

Cariou

Simonetta

et al. 2008

The Journal of Immunology

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“…Signi fi cant elevation (~20-fold over control) of autoantibodies such as anti-ssDNA can be seen at 4 weeks following the transfer of as few as 8 × 10 6 B6 donor CD4 T cells. More substantial elevations (~75-fold) are seen at 12 × 10 6 CD4 T cells ( 9 ) ; however, renal disease is histologically mild at this dose and typically 15-20 × 10 6 B6 CD4 T cells are required for signi fi cantly elevated glomerular scores ( 11 ) . By contrast, unfractionated DBA splenocytes containing as few as 12-14 × 10 6…”

Section: Introductionmentioning

confidence: 99%

The Parent-into-F1 Murine Model in the Study of Lupus-Like Autoimmunity and CD8 Cytotoxic T Lymphocyte Function

Soloviova

Puliaiev

Foster

et al. 2012

Methods in Molecular Biology

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The transfer of homozygous C57Bl/6 (B6) or DBA/2 (DBA) parental strain T cells into normal B6D2F1 mice in the parent-into-F1 (p → F1) model results in a graft-vs.-host disease (GVHD) that takes one of the following two forms: (a) acute GVHD seen with B6 → F1 mice and mediated by donor CD8 cytotoxic T cells that eliminate host lymphocytes and (b) a chronic lupus-like GVHD seen with DBA → F1 mice and mediated by donor CD4 T cell cognate help to autoreactive B cells resulting in autoantibody production and renal disease similar to human lupus. Importantly, these two phenotypes can be distinguished by flow cytometry as early as 2 weeks after donor cell transfer. The p → F1 model can be used to screen for agents that alter lupus development. Additionally, the model is useful for preclinical screening of biologic agents with immunomodulatory potential. Agents that selectively inhibit CD8 T cell function will convert acute GVHD to chronic GVHD in B6 → F1 mice. Conversely, agents that promote CD8 CTL function will convert chronic GVHD to acute GVHD in DBA → F1 mice. Agents that completely suppress T cell function will block both phenotypes. The model is also useful for examining the effects of T cell mutations by transferring mutant T cells into wild-type hosts and assessing the effects on disease phenotype. Differences observed from wild-type T cells → F1 can be directly ascribed to alterations in mutant T cell function. Because of the early 2-week phenotype development, the p → F1 model is well suited to screening of potential immunomodulatory therapeutic compounds and the assessment of T cell mutations on in vivo function.

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“…P→F1 aGVHD was induced with 50 3 10 6 unfractionated splenocytes from B6 wild-type (WT) or B6 IL-21R 2/2 donors injected i.v. into 6-8-wk old BDF1 mice, as described (34). In some experiments, the number of donor CD4 and CD8 T celquantified first by flow cytometry, and the donor cell number was adjusted so that the amount of CD8 and CD4 T cells in the IL-21R 2/2 donor inoculum was approximately equal to that of WT donor cells.…”

Section: Induction Of Graft-versus-host Disease and In Vivo Il-21 Trementioning

confidence: 99%

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model

Nguyen

Rus

Chen

et al. 2016

The Journal of Immunology

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IL-21 promotes B cell and CTL responses in vivo, conferring IL-21 with a role in both humoral and cellular responses. Because CTL can target and eliminate autoreactive B cells, we investigated whether IL-21R signaling in CD8 T cells would alter the expansion of autoreactive B cells in an autoimmune setting. We addressed this question using the parent→F1 murine model of acute and chronic (lupus-like) graft-versus-host disease (GVHD) as models of a CTL-mediated or T-dependent B cell–mediated response, respectively. Induction of acute GVHD using IL-21R–deficient donor T cells resulted in decreased peak donor CD8 T cell numbers and decreased CTL effector function due to impaired granzyme B/perforin and Fas/Fas ligand pathways and a phenotype of low-intensity chronic GVHD with persistent host B cells, autoantibody production, and mild lupus-like renal disease. CTL effector maturation was critically dependent on IL-21R signaling in Ag-specific donor CD8, but not CD4, T cells. Conversely, treatment of DBA/2J→F1 chronic GVHD mice with IL-21 strongly promoted donor CD8 T cell expansion and rescued defective donor anti-host CTLs, resulting in host B cell elimination, decreased autoantibody levels, and attenuated renal disease, despite evidence of concurrently enhanced CD4 help for B cells and heightened B cell activation. These results demonstrate that, in the setting of lupus-like CD4 T cell–driven B cell hyperactivity, IL-21 signaling on Ag-specific donor CD8 T cells is critical for CTL effector maturation, whereas a lack of IL-21R downregulates CTL responses that would otherwise limit B cell hyperactivity and autoantibody production.

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T Cell TRAIL Promotes Murine Lupus by Sustaining Effector CD4 Th Cell Numbers and by Inhibiting CD8 CTL Activity

Cited by 36 publications

References 63 publications

Heterospecific CD4 Help to Rescue CD8 T Cell Killers

Heterospecific CD4 Help to Rescue CD8 T Cell Killers

The Parent-into-F1 Murine Model in the Study of Lupus-Like Autoimmunity and CD8 Cytotoxic T Lymphocyte Function

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model

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