B cell-deficient NOD.H-2h4 mice have CD4+CD25+ T regulatory cells that inhibit the development of spontaneous autoimmune thyroiditis - PubMed (original) (raw)

B cell-deficient NOD.H-2h4 mice have CD4+CD25+ T regulatory cells that inhibit the development of spontaneous autoimmune thyroiditis

Shiguang Yu et al. J Exp Med. 2006.

Abstract

Wild-type (WT) NOD.H-2h4 mice develop spontaneous autoimmune thyroiditis (SAT) when given 0.05% NaI in their drinking water, whereas B cell-deficient NOD.H-2h4 mice are SAT resistant. To test the hypothesis that resistance of B cell-deficient mice to SAT was due to the activity of regulatory CD4+CD25+ T (T reg) cells activated if autoantigen was initially presented on non-B cells, CD25+ T reg cells were transiently depleted in vivo using anti-CD25. B cell-deficient NOD.H-2h4 mice given three weekly injections of anti-CD25 developed SAT 8 wk after NaI water. Thyroid lesions were similar to those in WT mice except there were no B cells in thyroid infiltrates. WT and B cell-deficient mice had similar numbers of CD4+CD25+Foxp3+ cells. Mice with transgenic nitrophenyl-specific B cells unable to secrete immunoglobulin were also resistant to SAT, and transient depletion of T reg cells resulted in severe SAT with both T and B cells in thyroid infiltrates. T reg cells that inhibit SAT were eliminated by day 3 thymectomy, indicating they belong to the subset of naturally occurring T reg cells. However, T reg cell depletion did not increase SAT severity in WT mice, suggesting that T reg cells may be nonfunctional when effector T cells are activated; i.e., by autoantigen-presenting B cells.

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Figures

Figure 1.

Figure 1.

Flow cytometric analysis of CD4+CD25+ splenic T cells from 6-wk-old WT (A), B cell–deficient (B), and NP Tg (C) NOD.H-2h4 mice, CD8+CD25+ splenic T cells from NP Tg (D) mice, and CD4+CD25+ splenic T cells from NP Tg mice given anti-CD25 2 (E) or 7 (F) d previously as analyzed by flow cytometry. Results are representative of 5–10 mice analyzed in each group. The percentages of CD25+ cells in the gated CD4+ or CD8+ cells are indicated in the top right of each panel.

Figure 2.

Figure 2.

Hematoxylin and eosin–stained thyroids from WT, B cell–deficient, and NP Tg NOD.H-2h4 mice 2 mo after NaI water. (A) WT mouse with 2+ SAT, (B) WT mouse with 4+ SAT, and (C) B cell–deficient mouse given rat Ig; severity score, 0. (D and E) B cell–deficient mice given anti-CD25; D, 1+; E, 2+. (F) Rat Ig–treated NP Tg mouse; severity score, 0. (G–J) NP Tg mice given anti-CD25; G, 2+; H, 3+; I and J, 4–5+. Magnification: A–G and J, 100; H and I, 40.

Figure 3.

Figure 3.

Immunohistochemical staining for CD4, CD8, and B220 in WT mice and in B cell–deficient and NP Tg mice given anti-CD25 beginning at 10 d of age as described in Materials and methods. All mice were given 0.05% NaI water at 8 wk of age. All infiltrating lymphocytes in B cell–deficient thyroids are CD4 and CD8+ T cells. WT and NP Tg thyroids also have many B220+ B cells. Magnification: 400.

Figure 4.

Figure 4.

CD4+CD25+ T cells from WT and B cell–deficient mice express similar amounts of Foxp3. (A) Expression of Foxp3 mRNA by CD4+CD25-depleted and CD4+CD25-enriched cells from 6–8-wk-old naive WT and B cell–deficient NOD.H-2h4 mice. There was no significant difference in expression of Foxp3 by CD25+ cells from WT and B cell–deficient mice (P > 0.3). (B) Spleen cells from WT and B cell–deficient mice express similar numbers of CD4+CD25+Foxp3+ cells when analyzed by flow cytometry using a Foxp3 staining kit as described in Materials and methods. Bars represent mean percentages of CD4+CD25+Foxp3+ cells from five individual 8-wk-old B cell–deficient (μ−/−) or WT mice. (C and D) Representative Foxp3 staining results for a B cell–deficient (C) or WT (D) mouse.

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