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Clin Exp Immunol. 2013 May;172(2):300-10. doi: 10.1111/cei.12051.

Human T cells depend on functional calcineurin, tumour necrosis factor-α and CD80/CD86 for expansion and activation in mice.

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  • 1Department of Immunopharmacology, Novo Nordisk A/S, Måløv, Denmark. hris@novonordisk.com

Abstract

Dysregulated T cells are a hallmark of several autoimmune and inflammatory diseases; thus, models to study human T cells in vivo are advantageous, but limited by lacking insight into human T cell functionality in mice. Using non-obese diabetic (NOD), severe combined immunodeficient (SCID) or recombination activating gene-1 (RAG1)(-/-) and interleukin-2 receptor gamma-chain (IL-2Rγ)(-/-) mice reconstituted with human peripheral blood mononuclear cells (PBMCs), we have studied the mechanisms of human T cell expansion and activation in mice. Injection of human PBMCs into mice caused consistent xeno-engraftment with polyclonal expansion and activation of functional human T cells and production of human cytokines. Human T cell expansion coincided with development of a graft-versus-host disease (GVHD)-like condition observed as weight loss, multi-organ immune infiltration and liver damage. CD8(+) T cells alone were sufficient for expansion and required for disease development; in contrast, CD4(+) T cells alone expanded but did not induce acute disease and, rather, exerted regulatory capacity through CD25(+)CD4(+) T cells. Using various anti-inflammatory compounds, we demonstrated that several T cell-activation pathways controlled T cell expansion and disease development, including calcineurin-, tumour necrosis factor-α and co-stimulatory signalling via the CD80/CD86 pathway, indicating the diverse modes of action used by human T cells during expansion and activation in mice as well as the pharmacological relevance of this model. Overall, these data provide insight into the mechanisms used by human T cells during expansion and activation in mice, and we speculate that PBMC-injected mice may be useful to study intrinsic human T cell functions in vivo and to test T cell-targeting compounds.

© 2012 Novo Nordisk A/S Clinical and Experimental Immunology © 2012 British Society for Immunology.

PMID:
23574326
[PubMed - indexed for MEDLINE]
PMCID:
PMC3628332
Free PMC Article

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