Foxp3+ regulatory T cells maintain immune homeostasis in the skin - PubMed (original) (raw)

Foxp3+ regulatory T cells maintain immune homeostasis in the skin

Jan C Dudda et al. J Exp Med. 2008.

Abstract

Cutaneous immune responses must be tightly controlled to prevent unwanted inflammation in response to innocuous antigens, while maintaining the ability to combat skin-tropic pathogens. Foxp3(+) regulatory T (T reg) cells are potent immune regulators and are found at high frequency in both human and mouse skin. Although T reg cells migrate to the skin and can dampen immune responses during experimentally induced inflammation or infection, the importance of cutaneous T reg cells for maintaining normal immune homeostasis in the skin has not been addressed. To selectively block T reg cell function in the skin, we restored the T reg cell compartment in Foxp3-deficient scurfy mice with cells whose ability to migrate to the skin was impaired because of targeted mutation of alpha-1,3-fucosyltransferase VII (Fut7). Although Fut7-deficient T reg cells were present at normal frequency and could function in all other tissues examined, these animals rapidly developed severe cutaneous inflammation. Thus, skin-resident T reg cell are essential for maintaining normal immune homeostasis at this site.

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Figures

Figure 1.

Figure 1.

T reg cells transferred into sf mice up-regulate cutaneous homing receptors and accumulate in the skin. (A) Homing receptor expression in LNs and spleen 4 wk after transfer of T reg cells into a neonatal sf mouse was compared with that in an 8-wk-old Foxp3gfp mouse by flow cytometry. Numbers indicate the frequency of positive cells among the Foxp3+ T reg cells. Plots are gated on total live cells (top left) or CD4+Foxp3+ cells (all other graphs). (B) Flow cytometry analysis of CD103 and Foxp3 expression by gated CD4+ T cells isolated from the indicated tissues 4 wk after T reg cell transfer into neonatal sf mice. Data are representative of three independent experiments.

Figure 2.

Figure 2.

Phenotypic and functional characterization of FuT7−/−-T reg cells. (A) Frequency of Foxp3+ T reg cells among CD4+ T cells in peripheral LNs and spleens of 8-wk-old WT (shaded bars) or FuT7−/− (open bars) mice. (B) Frequency of CD4+Foxp3+ T reg cells expressing the indicated homing receptors in peripheral LNs (PLN) or spleens of WT and FuT7−/− mice. Data in A and B are the mean and SD of values from three age-matched mice/group. Significance was measured using two-tailed, unpaired Student's t tests. *** indicates P < 0.0001; P > 0.05 for all other comparisons. (C) Proliferation of CD4+CD25− effector T cells as measured by CFSE dilution after 96 h of culture with CD4-depleted splenocytes in the presence or absence of anti-CD3 and -CD28 antibodies (top) and the indicated ratio of WT- or FuT7−/−-T reg cells (middle and bottom). Representative results of one out of two independent experiments.

Figure 3.

Figure 3.

Accumulation of FuT7−/−-T reg cells in the skin is selectively impaired. WT- (CD45.1+) and FuT7−/−- (CD45.2+) T reg cells were transferred into 2-d-old sf mice (CD45.1+CD45.2+), and tissue distribution was analyzed 6 wk later by flow cytometry analysis of CD45.1 and CD45.2 expression by gated CD4+ T cells isolated from the indicated tissues. Representative results of one out of three independent experiments.

Figure 4.

Figure 4.

Blocking T reg cell migration to the skin results in cutaneous inflammation. (A) Photomicrographs of hematoxylin and eosin–stained sections from skin, liver, and lung of sf mice left untreated (top; 21 d old) or given WT- (middle; 53 d old) or FuT7−/−- (bottom; 35 d old) T reg cells. Bars, 100 μm. (B) Flow cytometry analysis of CD44 and CD45RB expression by gated CD4+Foxp3− cells from pooled LNs and spleens of age-matched WT and sf mice (top; 21 d old) or sf mice given WT- or FuT7−/−-T reg cells (bottom; 35 d old). Numbers indicate the frequency of activated CD44high/CD45RBlow cells. (C) Flow cytometry analysis of CD45.1 and CD45.2 expression by gated CD4+ T cells isolated from the indicated tissues of CD45.1+sf mice given CD45.2+ WT- or FuT7−/−-T reg cells 5 wk before. Percentages indicate the frequency of CD45.2+ T reg cells among CD4+ cells. Data are representative of three to six experiments.

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References

    1. Bennett, C.L., J. Christie, F. Ramsdell, M.E. Brunkow, P.J. Ferguson, L. Whitesell, T.E. Kelly, F.T. Saulsbury, P.F. Chance, and H.D. Ochs. 2001. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27:20–21. - PubMed
    1. Khattri, R., T. Cox, S.A. Yasayko, and F. Ramsdell. 2003. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4:337–342. - PubMed
    1. Fontenot, J.D., M.A. Gavin, and A.Y. Rudensky. 2003. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4:330–336. - PubMed
    1. Kim, J.M., J.P. Rasmussen, and A.Y. Rudensky. 2007. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8:191–197. - PubMed
    1. Powrie, F., M.W. Leach, S. Mauze, L.B. Caddle, and R.L. Coffman. 1993. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int. Immunol. 5:1461–1471. - PubMed

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