Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


The Help of Autoantibody-Inducing CD4 T Cell and Antigen Cross-Presentation Are Required for the Full-Maturation of Cytotoxic T Lymphocyte and Subsequent Lupus Kidney Disease.

Miyazaki1,  Yumi, Tsumiyama1,  Ken, Shiozawa2,  Shunichi

Department of Biophysics, Kobe University Graduate School of Health Science, Kobe, Japan
Department of Biophysics, Kobe University Graduate School of Health Science/Department of Medicine, Kobe University Graduate School of Medicine/The Center for Rheumatic Diseases, Kobe University Hospital, Kobe, Japan

Objective:

A novel 'self-organized criticality theory' explaining the cause of systemic lupus erythematosus (SLE) of ours (Tsumiyama K. et al. PLoS ONE 4(12):e8382, 2009) shows that overstimulation of CD4+ T cell beyond its self-organized criticality results in de novo generation of autoantibody-inducing CD4+ T (aiCD4+ T) cell with T cell receptor (TCR) revision. The aiCD4+ T cells induced not only autoantibodies including rheumatoid factor (RF), anti-Sm and anti-dsDNA antibody but also full-matured cytotoxic T lymphocyte (CTL) via antigen cross-presentation, after which the CTL caused lupus kidney disease. Here we investigated the contribution of aiCD4+ T cell-help to the pathogenesis of immune tissue injury, and show that aiCD4+ T cell-help and antigen cross-presentation are both essentially required for generating full-matured effector CTL and subsequent lupus tissue injuries.

Methods:

BALB/c mice were immunized 12x with ovalbumin (OVA). The mice were depleted CD4+ T cells by treating anti-CD4 antibody 24 hours prior to 6x, 9x, and 12x immunization with OVA, and IFNg+CD8+ T cell in spleen and proteinuria were examined. The aiCD4+ T cell of the mice immunized 12x with keyhole limpet hemocyanin (KLH) was transferred into the CD4+ T cell-depleted mice immunized 8x with OVA, and IFNg+CD8+ T cell and proteinuria were examined. We also transferred pre-mature CD8+ T cell of the mice immunized 8x with OVA into the mice immunized 12x with KLH to induce aiCD4+ T cell. These recipient mice were immunized 1x with OVA and KLH, followed by treating with chloroquine to inhibit antigen cross-presentation.

Results:

In the mice immunized 12x with OVA, depletion of CD4+ T cells by treating anti-CD4 antibody abrogated the induction of IFNg-producing effector CD8+ T cell and lupus kidney disease. To test whether this CD4+ T cell-mediated help is mediated by aiT cells or antigen-specific T cells, we have transferred CD4+ T cells from mice immunized 12x with KLH into the CD4+ T cell-depleted BALB/c mice immunized 8x with OVA. The result showed that both immune tissue injury and OVA-specific IFNg+CD8+ T cells arose in these mice after transfer, indicating that aiCD4+ T cells with de novo TCR revision are required for the full-maturation of CD8+ T cell and lupus kidney disease. We next studied if aiCD4+ T cell could induce effector CTL and/or tissue injury in the absence of antigen cross-presentation or not, we transferred the pre-matured CD8+ T cells obtained from the mice immunized 8x with OVA, in which CTL was not full-matured, into the mice immunized 12x with KLH containing aiCD4+ T cells. Upon booster immunization 1x with KLH and OVA, aiCD4+ T cell, IFNg-producing effector CD8+ T cell (CTL) and proteinuria were all increased. However, when chloroquine which inhibits antigen cross-presentation was added, IFNg-producing effector CTL and proteinuria were both abolished, indicating that aiCD4+ T cell-help and antigen cross-presentation are required for the development of lupus kidney disease.

Conclusion:

The help of aiCD4+ T cell and antigen cross-presentation are sine qua non for the full-maturation of effector CTL and subsequent lupus kidney disease.

To cite this abstract, please use the following information:
Miyazaki, Yumi, Tsumiyama, Ken, Shiozawa, Shunichi; The Help of Autoantibody-Inducing CD4 T Cell and Antigen Cross-Presentation Are Required for the Full-Maturation of Cytotoxic T Lymphocyte and Subsequent Lupus Kidney Disease. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :867
DOI: 10.1002/art.28635

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