Cutting Edge: Autoimmune Disease in Day 3 Thymectomized Mice Is Actively Controlled by Endogenous Disease-Specific Regulatory T Cells

Abstract

Female B6AF1 mice thymectomized on day 3 (d3tx) develop autoimmune ovarian disease (AOD) and dacryoadenitis. It has been hypothesized that d3tx breaks tolerance by depleting late ontogeny regulatory T cells (Treg). We now report that Treg greatly expand over effector T cells in d3tx mice and adoptively suppress autoimmune disease in d3tx recipients. In the d3tx donors, Treg from ovarian lymph nodes (LN) preferentially suppress AOD and Treg from lacrimal gland LN preferentially suppress dacryoadenitis, suggesting they are strategically positioned for disease control. Indeed, the autologous disease in d3tx mice is dramatically enhanced by in vivo depletion of endogenous Treg. Moreover, normal 3-day-old mice possess Treg that suppress AOD and autoimmune gastritis as efficiently as adult cells. Thus, d3tx mice possess disease-relevant Treg of presumed neonatal origin. They accumulate in the regional LN and actively inhibit concurrent autoimmune disease; however, they cannot fully prevent autoimmune disease development.

Pathogenic Effector T Cell Enrichment Overcomes Regulatory T Cell Control and Generates Autoimmune Gastritis

“…Our results confirm those published by Bandeira and colleagues (21) showing that CD4 ϩ CD25 ϩ Tregs from 3dTx mice can inhibit inflammatory bowel disease, and more recently by Tung and colleagues (34) showing the presence of functional Tregs in a model of thymectomy-induced oophoritis.…”

“…Actually, all immunodeficient recipients that received CD25-depleted LN cells from gastritic donors showed signals of severe disease, while only 60% of recipients receiving total LN from gastritic donors showed gastritis with parietal cell destruction. This viewpoint is supported by recent data showing that Treg depletion in adult B6AF1 3dTx mice results in a much severe oophoritis (34).…”

Increased Susceptibility to Autoimmune Gastritis in Thymic Stromal Lymphopoietin Receptor-Deficient Mice

“…These data suggested that the enhanced proliferative capacity of CD4 + T cells in a Th1-dominant autoimmune setting may overcome a deficiency of direct action of TSLP on CD4 + T cells. In adult NTx mice, CD4 + Foxp3 + Tregs were observed in the periphery, as described (7)(8)(9). We also found that 12-wk-old NTx-TSLPR 2/2 mice had a number of CD4 + Foxp3 + Tregs in the periphery, comparable to those found in NTx-TSLPR +/+ mice (data not shown).…”

“…NTx mice possess disease-relevant CD4 + CD25 + regulatory T cells (Tregs), but these Tregs cannot fully prevent autoimmune disease development (7)(8)(9). Adult NTx mice frequently develop AIG, showing lymphocytic infiltration with selective loss of parietal and chief cells from the gastric mucosa, as well as production of autoantibodies to parietal cells (10).…”

Regulatory T Cells Suppress Innate Immunity in Kidney Ischemia-Reperfusion Injury

“…[22][23][24] Administration of PC61 (300 g intravenously) significantly decreased (approximately 50%) spleen, kidney, and blood Tregs 5 d after injection compared with mice treated with control IgG (300 g intravenously; Figure 1, A through E). This dosing strategy was chosen on the basis of the kinetic analysis of single-dose PC61 on FoxP3 ϩ Tregs in C57Bl/6 mice.…”