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

• Published in: Clinical and experimental immunology Vol. 172; no. 2; pp. 300 - 310
• Main Authors: Søndergaard, H., Kvist, P. H., Haase, C.
• Format: Journal Article
• Language: English
• Published: England Blackwell Science Inc 01.05.2013
• Subjects: Animals; B7-1 Antigen - metabolism; B7-2 Antigen - metabolism; calcineurin; Calcineurin - metabolism; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - transplantation; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - transplantation; Cell Proliferation; CTLA‐4; Graft vs Host Disease - immunology; graft‐versus‐host disease; Homeodomain Proteins - genetics; humanized mice; Humans; Interleukin Receptor Common gamma Subunit - genetics; Interleukin-2 Receptor alpha Subunit - metabolism; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - transplantation; Lymphocyte Activation; Mice; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; NOD.scid IL‐2Rγ; Original; Transplantation, Heterologous; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/cei.12051

Summary 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.