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Distinct gene signature revealed in white blood cells, CD4+ and CD8+ T cells in (NZBx NZW) F1 lupus mice after tolerization with anti-DNA Ig peptide

Genes & Immunity volume 11, pages 294–309 (2010)Cite this article

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Abstract

Tolerizing mice polygenically predisposed to lupus-like disease (NZB/NZW F1 females) with a peptide mimicking anti-DNA IgG sequences containing MHC class I and class II T cell determinants (pConsensus, pCons) results in protection from full-blown disease attributable in part to the induction of CD4+CD25+Foxp3+ and CD8+Foxp3+ regulatory T cells. We compared 45 000 murine genes in total white blood cells (WBC), CD4+ T cells, and CD8+ T cells from splenocytes of (NZBxNZW) F1 lupus-prone mice tolerized with pCons vs untreated naïve mice and found two-fold or greater differential expression for 448 WBC, 174 CD4, and 60 CD8 genes. We identified differentially expressed genes that played roles in the immune response and apoptosis. Using real-time PCR, we validated differential expression of selected genes (IFI202B, Bcl2, Foxp3, Trp-53, CCR7 and IFNar1) in the CD8+T cell microarray and determined expression of selected highly upregulated genes in different immune cell subsets. We also determined Smads expression in different immune cell subsets, including CD4+ T cells and CD8+ T cells, to detect the effects of TGF-β, known to be the major cytokine that accounts for the suppressive capacity of CD8+ Treg in this system. Silencing of anti-apoptotic gene Bcl2 or interferon genes (IFI202b and IFNar1 in combination) in CD8+ T cells from tolerized mice did not affect the expression of the other selected genes. However, silencing of Foxp3 reduced expression of Foxp3, Ifi202b and PD1—all of which are involved in the suppressive capacity of CD8+ Treg in this model.

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Acknowledgements

We thank the UCLA flow core facility for FACS analysis and cell sorting, Fanny Ebling for pCons tolerization, Vineet Dixit for computational assistance in figure drawing, and Dr Desmond Smith's lab for the real-time PCR. This study was supported by NIH Grants AR54034, AI 083894, AI65645 to RPS, AR53239 to ALC, AI46776 to BHH and UCLA Senate Core Grant and Southern California Arthritis Foundation (SCAF) grant to BHH, and RPS, and gifts from the Maltz and Horchow families and from Jeanne Rappaport.

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  1. Division of Rheumatology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA, USA

    R P Singh, R Dinesh, A La Cava & B H Hahn

  2. Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA, USA

    D Elashoff

  3. Division of Hematology and Oncology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA, USA

    S de Vos

  4. Genome Explorations Inc, Memphis, TN, USA

    R J Rooney & D Patel

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Correspondence to R P Singh.

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Dr Divyen Patel, PhD and Dr Robert J Rooney, PhD, are employed at Genome Explorations Inc., Memphis, TN, USA. All other authors are employed at UCLA, Los Angeles, CA, USA and have no conflict of interest. Drs. Hahn, La Cava and Singh have a patent through the University of California, Los Angeles for the use of pCons as an immune modulator in systemic lupus erythematosus.

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Singh, R., Dinesh, R., Elashoff, D. et al. Distinct gene signature revealed in white blood cells, CD4+ and CD8+ T cells in (NZBx NZW) F1 lupus mice after tolerization with anti-DNA Ig peptide. Genes Immun 11, 294–309 (2010). https://doi.org/10.1038/gene.2010.6

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