RPGN is T-cell mediated and can recur after kidney transplantation. T-cell receptor stimulation leads to intracellular signaling events ultimately causing activation of transcription factors such as NF-kappa B. We now examined T-cell specific ablation of IKK2 or NEMO in an RPGN model.

T-cell specific ablation of IKK2 or NEMO was achieved through deletion of IKK2or NEMO alleles by Cre-recombinase under control of the CD4cre transgene. NTN-antiserum was injected and functional parameters were determined during a 10-day observation period. T cells, Th1, Th17 and Treg infiltration into the kidney were analysed by FACS and kidney chemokine expression was determined by RT-PCR. Transcriptome analysis was performed of CD4+ T-cells isolated from spleens before and after RPGN induction.

Nephritic CD4creIKK2fLfL and CD4creNEMOfLfL mice had increased glomerular crescents at day 10 when compared to nephritic CD4cremice. Although the percentage of CD4+ T cells infiltrating kidneys was not different between the groups further analysis showed significantly reduced Tregs but a significant increase in Th1- and Th17-cells in CD4creIKK2fLfL and CD4creNEMOfLfL animals. Renal expression of cytokines and chemokines, IL-1β, CCL2 and CCL20 was significantly increased. Transcriptome analysis of CD4+ splenocytes was performed. Volcano plot revealed 97 genes differentially down- and 120 genes up-regulated in CD4+ splenocytes of nephritic mice in all groups examined when compared with non-nephritic controls. The results of distant regulatory elements (DiRE) analysis showed IKK2 and NEMO dependent differential transcription factors activation.

Our data demonstrate that ablation of IKK2 or NEMO specifically in CD4+ T-cells significantly increased Th1- and Th17-positive T cells infiltrating kidneys after RPGN. By combining microarray gene expression and bioinformatics analyses we have identified genes involved in T cell proliferation and differentiation that were differentially expressed between IKK2 and NEMO deficient CD4+ T-cells. We propose that better understanding the role of IKK2 and NEMO in NF-kappa B dependent T-cell regulation will help to recognize the role of IKK2- and NEMO- kinase inhibitors in the clinical application in patients with recurrence of glomerulonephritis.

CITATION INFORMATION: Thaiss F, Huang J, Chen M, Paust H, Zahner G, Alawi M, Geffers R, Guo L. Transcriptome Analysis of CD4-Lymphocyte Specifically Deleted of IKKbeta or NEMO in an Experimental Model of Rapid Progressive Glomerulonephritis (RPGN). Am J Transplant. 2017;17 (suppl 3).

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