The Presence and Preferential Activation of Regulatory T Cells Diminish Adoptive Transfer of Autoimmune Diabetes by Polyclonal Nonobese Diabetic (NOD) T Cell Effectors into NSG versus NOD-scid Mice.
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 γ-chain (Il-2rγ)-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-2rγ(null)-NSG versus Il-2rγ-intact standard NOD-scid recipients. In contrast, NOD-derived monoclonal/oligoclonal TCR transgenic β 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 β 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.
The Jackson Laboratory, Bar Harbor, ME 04609;
Maximiliano
M
Presa
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226; and.
Yi-Guang
YG
Chen
The Jackson Laboratory, Bar Harbor, ME 04609;
Alexandra E
AE
Grier
The Jackson Laboratory, Bar Harbor, ME 04609;
Edward H
EH
Leiter
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655.
Michael A
MA
Brehm
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655.
Dale L
DL
Greiner
The Jackson Laboratory, Bar Harbor, ME 04609;
Leonard D
LD
Shultz
The Jackson Laboratory, Bar Harbor, ME 04609; dave.serreze@jax.org.
David V
DV
Serreze
D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000628:therapy*; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000096:biosynthesis; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation
D053450:Glucocorticoid-Induced TNFR-Related Protein; D015375:Receptors, Interleukin-2; C106544:Tnfrsf18 protein, mouse