title: Human T cells depend on functional calcineurin, tumour necrosis factor-α and CD80/CD86 for expansion and activation in mice.
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.
authors.affiliation: Department of Immunopharmacology, Novo Nordisk A/S, Måløv, Denmark. hris@novonordisk.com
authors.forename: H
authors.initials: H
authors.lastname: Søndergaard
authors.forename: P H
authors.initials: PH
authors.lastname: Kvist
authors.forename: C
authors.initials: C
authors.lastname: Haase
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D019703:Calcineurin / Q000378:metabolism; D049109:Cell Proliferation; D006086:Graft vs Host Disease / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018398:Homeodomain Proteins; D053631:Interleukin Receptor Common gamma Subunit; D053645:Interleukin-2 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha; C064658:RAG-1 protein; D019703:Calcineurin