CD8+ T Cells Negatively Regulate IL-4–Dependent, IgG1-Dominant Posttransplant Alloantibody Production

Zimmerer, Jason M.; Pham, Thomas; Sanders, Virginia M.; Bumgardner, Ginny L.

doi:10.4049/jimmunol.1001655

Cited by 20 publications

(36 citation statements)

References 54 publications

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“…This reduction in alloantibody was accompanied by delayed allograft rejection in CD8-deficient Jα18 KO recipients (MST= day 17) compared to CD8-sufficient Jα18 KO recipients (MST= day 10; p<0.001). Serial analysis of alloantibody levels in CD8-depleted WT and Jα18 KO recipients showed both exhibited peak circulating alloantibody levels on day 14-21 posttransplant (data not shown), consistent with our previous studies (14). Therefore, the difference in quantity of alloantibody between the two groups is not due to a difference in the kinetics of alloantibody production.…”

Section: Resultssupporting

confidence: 91%

“…AT of WT (IL-4 + ) CD4 + T cells into CD8-depleted IL-4 KO mice restored alloantibody production but not to levels expected in CD8-depleted WT recipients (14). This suggests that other IL-4 + cells are required for high alloantibody production.…”

Section: Resultsmentioning

confidence: 99%

“…injection of 100 μg of mAb (clone 53.6.72; day -2,-1), as described (14). Depletion was confirmed through flow cytometric analysis of recipient peripheral blood lymphocytes.…”

Section: Methodsmentioning

confidence: 99%

“…Recipient serum was tested for allospecificity first by incubation with allogeneic FVB/N target splenocytes, as previously described (14). The percent binding of total IgG to splenocyte targets was determined by a second incubation with FITC-conjugated goat anti-mouse IgG Fc (Organon Teknika, Durham, NC) and analysis by flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

“…Using a well characterized in vivo model of posttransplant alloantibody production, we provided first evidence supporting a pivotal role for IFN-γ + CD8 + T cells in the inhibition of posttransplant IgG1 (IL-4-dependent) alloantibody production, in part, by downregulating the development of IL-4 + CD4 + T cells (14) and, in part, by killing IgG1 + B cells (15). Our data raise the possibility that current agents suppress T cell immune pathways which both promote (CD4 + T cells) and downregulate (CD8 + T cells) alloantibody production.…”

Section: Introductionmentioning

confidence: 99%

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Critical Role of NKT Cells in Posttransplant Alloantibody Production

Zimmerer

Swamy

Sanghavi

et al. 2014

American Journal of Transplantation

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We previously reported that posttransplant alloantibody production in CD8-deficient hosts is IL-4+CD4+ T cell-dependent and IgG1 isotype-dominant. The current studies investigated the hypothesis that IL-4-producing NKT cells contribute to maximal alloantibody production. To investigate this, alloantibody levels were examined in CD8-deficient wild-type, CD1d KO and Jα18 KO transplant recipients. We found that the magnitude of IgG1 alloantibody production was critically dependent on the presence of type I NKT cells, which are activated by day 1 posttransplant. Unexpectedly, type I NKT cell contribution to enhanced IgG1 alloantibody levels was IFN-γ-dependent and IL-4-independent. Cognate interactions between Type I NKT and B cells alone do not stimulate alloantibody production. Instead, NKT cells appear to enhance maturation of IL-4+CD4+ T cells. To our knowledge, this is the first report to substantiate a critical role for type I NKT cells in enhancing in vivo antibody production in response to endogenous antigenic stimuli.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

“…injection of 100 μg of mAb (clone 53.6.72; day -2,-1), as described (14). Depletion was confirmed through flow cytometric analysis of recipient peripheral blood lymphocytes.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Critical Role of NKT Cells in Posttransplant Alloantibody Production

Zimmerer

Swamy

Sanghavi

et al. 2014

American Journal of Transplantation

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Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts

Kohei

Tanaka

Tanabe

et al. 2016

Kidney International

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While the incidence of antibody-mediated kidney graft rejection has increased, the key cellular and molecular participants underlying this graft injury remain unclear. Rejection of kidney allografts in mice lacking the chemokine receptor CCR5 is dependent on production of donor-specific antibody. Here we determine if cells expressing cytotoxic function contributed to antibody-mediated kidney allograft rejection in these recipients. Wild type C57BL/6, B6.CCR5−/− and B6.CD8−/−/CCR5−/− mice were transplanted with complete MHC mismatched A/J kidney grafts and intra-graft inflammatory components were followed to rejection. B6.CCR5−/− and B6.CD8−/−/CCR5−/− recipients rejected kidney allografts by day 35 whereas 65% of allografts in wild type recipients survived past day 80 post-transplant. Rejected allografts in wild-type C57BL/6, B6.CCR5−/− and B6.CD8−/−/CCR5−/− recipients expressed high levels of VCAM-1 and MMP7 mRNA that was associated with high serum titers of donor-specific antibody. High levels of perforin and granzyme B mRNA expression peaked on day 6 post-transplant in allografts in all recipients, but were absent in isografts. Depletion of natural killer cells in B6.CD8−/−/CCR5−/− recipients reduced this expression to background levels and promoted the long-term survival of 40% of the kidney allografts. Thus, natural killer cells have a role in increased inflammation during antibody-mediated kidney allograft injury and in rejection of the grafts.

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The longitudinal kinetics of AAV5 vector integration profiles and evaluation of clonal expansion in mice

Ismail,

Witt,

Bouwman

et al. 2024

Molecular Therapy - Methods & Clinical Development

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CD8+ T Cells Negatively Regulate IL-4–Dependent, IgG1-Dominant Posttransplant Alloantibody Production

Abstract: Material Supplementary 5.DC1http://www.jimmunol.org/content/suppl/2010/11/17/jimmunol.100165References

Cited by 20 publications

References 54 publications

Critical Role of NKT Cells in Posttransplant Alloantibody Production

Critical Role of NKT Cells in Posttransplant Alloantibody Production

Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts

The longitudinal kinetics of AAV5 vector integration profiles and evaluation of clonal expansion in mice

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