Induced pluripotent stem cell macrophages present antigen to proinsulin-specific T cell receptors from donor-matched islet-infiltrating T cells in type 1 diabetes

Abstract

Aims/hypothesisType 1 diabetes is an autoimmune disorder characterised by loss of insulin-producing beta cells of the pancreas. Progress in understanding the cellular and molecular mechanisms underlying the human disease has been hampered by a dearth of appropriate human experimental models. We previously reported the characterisation of islet-infiltrating CD4+ T cells from a deceased organ donor who had type 1 diabetes.MethodsInduced pluripotent stem cell (iPSC) lines derived from the above donor were differentiated into CD14+ macrophages and tested for their capacity to present antigen to T cell receptors (TCRs) derived from islet-infiltrating CD4+ T cells from the same donor.ResultsThe iPSC macrophages displayed typical macrophage morphology, surface markers (CD14, CD86, CD16 and CD11b) and were phagocytic. In response to IFNγ treatment, iPSC macrophages upregulated expression of HLA class II, a characteristic that correlated with their capacity to present epitopes derived from proinsulin C-peptide to a T cell line expressing TCRs derived from islet-infiltrating CD4+ T cells of the original donor. T cell activation was specifically blocked by anti-HLA-DQ antibodies but not by antibodies directed against HLA-DR.Conclusions/interpretationThis study provides a proof of principle for the use of iPSC-derived immune cells for modelling key cellular interactions in human type 1 diabetes.Electronic supplementary materialThe online version of this article (10.1007/s00125-019-04988-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Macrophages Derived From Human Induced Pluripotent Stem Cells: The Diversity of Protocols, Future Prospects, and Outstanding Questions

“…Because of FGF2 capacity to maintain cell pluripotency and antagonize BMP4, many investigators pay special attention to exclude FGF2 from culture medium during the first 2 to 3 days of iPSC differentiation ( Table 5 ) or even 3 to 5 days prior to the start of iPSC differentiation ( Ackermann et al, 2018 ). However, some authors did add FGF2 to cell cultures at differentiation day 0, either in reduced concentrations (EB-S protocol, Lachmann et al, 2015 ) or in combination with BMP4 (EB-F protocol, Joshi et al, 2019 ). A few EB-F protocols did not use FGF2 at all ( Xu et al, 2012 ; Buchrieser et al, 2017 ; Lopez-Yrigoyen et al, 2020 ).…”

Modeling Type 1 Diabetes Using Pluripotent Stem Cell Technology

“…For this reason, we investigated the generation of iPSC derived macrophages from individuals with T1D. We were able to demonstrate that these antigen presenting cells had mature functionality and were able to process and present islet lysate and purified synthetic C-peptide to autologous islet infiltrating CD4+ T-cells ( 44 ) ( Table 1 ). Clearly, the major benefit of the iPSC system is the capacity to exactly match the HLA alleles of antigen presenting cells (APCs) to donor derived T cells.…”

“…However, this path also presents its own challenges, including the phenomenon of T cell exhaustion ( 82 , 109 , 110 ) and the issue of whether the TCR repertoire of T cells in circulation reflects that of autoreactive T cells present with the islets ( 105 , 108 ). Ideally, an in vitro model would incorporate T cells isolated from islets of T1D individuals ( 44 , 104 , 107 ), a scenario that would limit the scope of such a model to deceased tissue donors.…”

The Immune-Modulatory Properties of iPSC-Derived Antigen-Presenting Cells

“…Although the functionality of iPSC-derived macrophages in the context of cytokine secretion, chemotaxis, phagocytosis, as well as the antimicrobial activity has been studied in detail, the antigen-presenting properties of iPSC-derived macrophages remain mainly elusive. However, promising data has recently been provided by Joshi et al [45] who showed that human iPSC-derived macrophages can indeed present antigens to autologous, islet-infiltrating CD4 + T cells of a diabetes type I patient. Moreover, our own unpublished results indicate that iPSC-derived macrophages are also able to present viral antigens and thereby expand autologous antigen-specific CD8 + T cells.…”