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. 2002 Apr 1;195(7):855-67.
doi: 10.1084/jem.20012000.

Resident skin-specific gammadelta T cells provide local, nonredundant regulation of cutaneous inflammation

Michael Girardi  1 , Julia Lewis, Earl Glusac, Renata B Filler, Liping Geng, Adrian C Hayday, Robert E Tigelaar
Affiliations

Resident skin-specific gammadelta T cells provide local, nonredundant regulation of cutaneous inflammation

Michael Girardi et al. J Exp Med. .

Abstract

The function of the intraepithelial lymphocyte (IEL) network of T cell receptor (TCR) gammadelta(+) (Vgamma5(+)) dendritic epidermal T cells (DETC) was evaluated by examining several mouse strains genetically deficient in gammadelta T cells (delta(-/-) mice), and in delta(-/-) mice reconstituted with DETC or with different gammadelta cell subpopulations. NOD.delta(-/-) and FVB.delta(-/-) mice spontaneously developed localized, chronic dermatitis, whereas interestingly, the commonly used C57BL/6.delta(-/-) strain did not. Genetic analyses indicated a single autosomal recessive gene controlled the dermatitis susceptibility of NOD.delta(-/-) mice. Furthermore, allergic and irritant contact dermatitis reactions were exaggerated in FVB.delta(-/-), but not in C57BL/6.delta(-/-) mice. Neither spontaneous nor augmented irritant dermatitis was observed in FVB.beta(-/-) delta(-/-) mice lacking all T cells, indicating that alphabeta T cell-mediated inflammation is the target for gammadelta-mediated down-regulation. Reconstitution studies demonstrated that both spontaneous and augmented irritant dermatitis in FVB.delta(-/-) mice were down-regulated by Vgamma5(+) DETC, but not by epidermal T cells expressing other gammadelta TCRs. This study demonstrates that functional impairment at an epithelial interface can be specifically attributed to absence of the local TCR-gammadelta(+) IEL subset and suggests that systemic inflammatory reactions may more generally be subject to substantial regulation by local IELs.

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Figures

Figure 5.
Figure 5.
Reconstitution with Vγ5+ E17 fetal thymocytes (DETC precursors) is sufficient to prevent spontaneous dermatitis in FVB.δ−/− mice. (A) Baseline ear thickness of 10-wk-old FVB mice (n = 4–5 mice per group; data expressed as mean ±SE): unreconstituted FVB.δ−/− mice (positive controls); normal FVB.δ+ mice (negative controls); FVB.δ−/− mice inoculated (intraperitoneally) as 1–3 d old neonates either with flow cytometry-purified (98% pure) Vγ5+ E17 fetal thymocytes (8 × 104 105 cells), or with flow cytometry-purified Vγ5– E17 fetal thymocytes (2 × 106 cells). (B) Flow cytometric analysis of epidermal cell suspensions individually prepared from the ears of these same mice. n = 4–5 mice per group. Data is expressed as the mean percentage (±SE) of epidermal cells which stained as Vγ5+ DETC (F536+ GL3+; black bars), as Vγ5− γδ T cells (F536+ GL3+; white bars), or as αβ T cells (CD3+ GL3−; hatched bars). nd, non-detected. (C) Flow cytometric analyses of epidermal cell suspensions prepared from the ears of a representative from each of the above four groups of mice. Numbers in lower right-hand corners of the quadrants of the contour plots indicate percentages of live cells within those quadrants.
Figure 1.
Figure 1.
Spontaneous dermatitis in the ears of unmanipulated δ−/− mice is strain dependent. (A) 12-wk-old NOD.δ−/− mice exhibit spontaneous ear erythema, while (B) age-matched NOD controls mice do not. (C) H&E stained section (original magnification: 200×) of a 12-wk NOD.δ−/− ear shows histologic features of chronic dermatitis, including increased numbers of mast cells (shown in left inset, Giemsa stain, Original magnification: 400×; and right inset, H&E stain. Original magnification: 400×). (D) H&E section of uninflamed ear of 12-wk-old NOD control mouse. (E) Increased baseline ear thickness of unmanipulated 12-wk-old NOD.δ−/− and FVB.δ−/− mice compared with age-matched NOD and FVB controls contrasts with the indistinguishable baseline ear thickness measured in 12-wk-old C57BL/6.δ−/− and C57BL/6 control mice (n = 12–18 mice per group). Data expressed as mean ±SE.
Figure 1.
Figure 1.
Spontaneous dermatitis in the ears of unmanipulated δ−/− mice is strain dependent. (A) 12-wk-old NOD.δ−/− mice exhibit spontaneous ear erythema, while (B) age-matched NOD controls mice do not. (C) H&E stained section (original magnification: 200×) of a 12-wk NOD.δ−/− ear shows histologic features of chronic dermatitis, including increased numbers of mast cells (shown in left inset, Giemsa stain, Original magnification: 400×; and right inset, H&E stain. Original magnification: 400×). (D) H&E section of uninflamed ear of 12-wk-old NOD control mouse. (E) Increased baseline ear thickness of unmanipulated 12-wk-old NOD.δ−/− and FVB.δ−/− mice compared with age-matched NOD and FVB controls contrasts with the indistinguishable baseline ear thickness measured in 12-wk-old C57BL/6.δ−/− and C57BL/6 control mice (n = 12–18 mice per group). Data expressed as mean ±SE.
Figure 2.
Figure 2.
Spontaneous cutaneous inflammation in crosses of susceptible NOD.δ−/− with resistant C57BL/6 δ−/− mice. NOD.δ−/− and C57BL/6.δ−/− mice were bred to produce F1, F2, and (F1 × NOD) backcross (BC) offspring. Each symbol represents an individual animal, and data is shown separately for females (F) and males (M) of each group. Mean baseline ear thickness ±SD is given for each group of animals.
Figure 3.
Figure 3.
Increased allergic and irritant contact dermatitis reactions in δ−/− versus wild-type mice are dependent on genetic background. (A) ACD responses 24 h after DNFB challenge of DNFB-immune control and δ−/− FVB and C57BL/6 mice (n = 10–20 mice per group; data expressed as mean ±SE). Ear swelling above baseline in FVB.δ–/– mice was more than twice that in FVB control mice (P < 0.0001), while responses of C57BL/6.δ−/− and control mice were indistinguishable. N.S., no significant difference. (B) Irritant contact dermatitis responses 24 h after TPA challenge of FVB and C57BL6 δ−/− and control mice. n = 10–15 mice per group; data expressed as mean ±SE. Ear swelling above baseline of FVB.δ−/− mice was nearly twice that of FVB mice (P < 0.0001), while equivalent responses were seen in C57BL/6.δ−/− and C57BL/6 mice. (C) Adoptive transfer of graded numbers of lymph node cells from DNFB-sensitized FVB.δ−/− or FVB donors to naive adult FVB recipients results in equivalent ear swelling responses 24 h after DNFB challenge.
Figure 4.
Figure 4.
Increased baseline ear thickness (spontaneous dermatitis) and augmented irritant contact dermatitis responses to TPA in FVB.δ−/− mice are dependent on the presence of αβ T cells. (A) Baseline ear thickness is higher in 10-wk-old FVB.δ−/− mice than in FVB controls; however, age-matched FVB.β−/−δ−/− mice (deficient in both αβ+ and γδ+ T cells) exhibit no difference in baseline ear thickness relative to control FVB mice (n = 10 mice per group; data expressed as mean ±SE). (B) Irritant contact reactions of the same mice 24 h after challenge with TPA. As in Fig. 2 B, irritant reactions (shown as ear swelling above baseline) are significantly greater in FVB.δ−/− mice than in FVB controls; however, ear swelling in FVB.β−/−δ−/− mice is not significantly different from that in FVB controls. (C) 6 d after TPA challenge, FVB.δ−/− ears demonstrate histologic features of subacute dermatitis, while ears of representative FVB controls and FVB.β−/−δ−/− mice exhibit equivalent, and much less striking, evidence of inflammation (H&E, original magnification: 200×).
Figure 4.
Figure 4.
Increased baseline ear thickness (spontaneous dermatitis) and augmented irritant contact dermatitis responses to TPA in FVB.δ−/− mice are dependent on the presence of αβ T cells. (A) Baseline ear thickness is higher in 10-wk-old FVB.δ−/− mice than in FVB controls; however, age-matched FVB.β−/−δ−/− mice (deficient in both αβ+ and γδ+ T cells) exhibit no difference in baseline ear thickness relative to control FVB mice (n = 10 mice per group; data expressed as mean ±SE). (B) Irritant contact reactions of the same mice 24 h after challenge with TPA. As in Fig. 2 B, irritant reactions (shown as ear swelling above baseline) are significantly greater in FVB.δ−/− mice than in FVB controls; however, ear swelling in FVB.β−/−δ−/− mice is not significantly different from that in FVB controls. (C) 6 d after TPA challenge, FVB.δ−/− ears demonstrate histologic features of subacute dermatitis, while ears of representative FVB controls and FVB.β−/−δ−/− mice exhibit equivalent, and much less striking, evidence of inflammation (H&E, original magnification: 200×).
Figure 6.
Figure 6.
Reconstitution withVγ5+ E17 fetal thymocytes (DETC precursors), but not Vγ5− adult peripheral lymph node γδ cells, down-regulates both spontaneous and irritant dermatitis in FVB.δ−/− mice. (A) Baseline ear thickness and (B) irritant ear swelling reactions 24 h after three weekly applications of TPA in groups of 10-wk-old FVB mice (n = 4–5 mice per group; data expressed as mean ±SE): unreconstituted FVB.δ−/− mice (positive controls); normal FVB.δ+ mice (negative controls); FVB.δ–/– mice reconstituted as 1–3-d-old neonates with either 8 × 104 flow cytometry-purified (98% pure) Vγ5+ fetal thymocytes from E17 FVB δ+ donors, or 107 peripheral lymph node cells (determined by flow cytometry to contain 1.5 × 106 Vγ5− γδ cells) obtained from 8-wk-old FVB.β−/− donors. (C) Flow cytometric analyses of epidermal cell suspensions prepared from the ears of a representative from each of the above four groups of mice. Numbers in lower right-hand corners of the quadrants of the contour plots indicate percentages of live cells within those quadrants.
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