Journal
JOURNAL OF IMMUNOLOGY
Volume 195, Issue 7, Pages 3011-3019Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1402446
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Funding
- National Institutes of Health [DK46266, DK95735, DK77443, AI46629-13, DK089572, AI112321]
- Juvenile Diabetes Research Foundation
- American Diabetes Association
- Helmsley Charitable Trust [2014PG-T1D048, 2012PG-T1D018]
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NOD-scid.Il2rg(null) (NSG) mice are currently being used as recipients to screen for pathogenic autoreactive T cells in type 1 diabetes (T1D) patients. We questioned whether the restriction of IL-2R gamma-chain (Il-2r gamma)-dependent cytokine signaling only to donor cells in NSG recipients differently influenced the activities of transferred diabetogenic T cells when they were introduced as a monoclonal/oligoclonal population versus being part of a polyclonal repertoire. Unexpectedly, a significantly decreased T1D transfer by splenocytes from prediabetic NOD donors was observed in Il-2r gamma(null)-NSG versus Il-2r gamma-intact standard NOD-scid recipients. In contrast, NOD-derived monoclonal/oligoclonal TCR transgenic beta cell-autoreactive T cells in either the CD8 (AI4, NY8.3) or CD4 (BDC2.5) compartments transferred disease significantly more rapidly to NSG than to NOD-scid recipients. The reduced diabetes transfer efficiency by polyclonal T cells in NSG recipients was associated with enhanced activation of regulatory T cells (Tregs) mediated by NSG myeloid APC. This enhanced suppressor activity was associated with higher levels of Treg GITR expression in the presence of NSG than NOD-scid APC. These collective results indicate NSG recipients might be efficiently employed to test the activity of T1D patient-derived beta cell-autoreactive T cell clones and lines, but, when screening for pathogenic effectors within polyclonal populations, Tregs should be removed from the transfer inoculum to avoid false-negative results.
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