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Epithelia Use Butyrophilin-like Molecules to Shape Organ-Specific γ δ T Cell Compartments

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ABSTRACT

Many body surfaces harbor organ-specific γδ T cell compartments that contribute to tissue integrity. Thus, murine dendritic epidermal T cells (DETCs) uniquely expressing T cell receptor (TCR)-Vγ5 chains protect from cutaneous carcinogens. The DETC repertoire is shaped by Skint1, a butyrophilin-like (Btnl) gene expressed specifically by thymic epithelial cells and suprabasal keratinocytes. However, the generality of this mechanism has remained opaque, since neither Skint1 nor DETCs are evolutionarily conserved. Here, Btnl1 expressed by murine enterocytes is shown to shape the local TCR-Vγ7+ γδ compartment. Uninfluenced by microbial or food antigens, this activity evokes the developmental selection of TCRαβ+ repertoires. Indeed, Btnl1 and Btnl6 jointly induce TCR-dependent responses specifically in intestinal Vγ7+ cells. Likewise, human gut epithelial cells express BTNL3 and BTNL8 that jointly induce selective TCR-dependent responses of human colonic Vγ4+ cells. Hence, a conserved mechanism emerges whereby epithelia use organ-specific BTNL/Btnl genes to shape local T cell compartments.

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Villin-Specific Btnl1 Induction Rescues Vγ7+ IEL In Vivo(A–D) Week 7–13 (adult) or day 7–21 (pups) mice of indicated genotypes on a Btnl1−/− background were administered Dox (1 mg/ml, 2% sucrose) or control water (2% sucrose) for times indicated, and IELs were analyzed by flow cytometry. n ≥ 5 (A and B); n ≥ 6 (C and D).(E) Comparative cell-surface phenotypes of Vγ7+ IELs from week 4–5 WT mice and animals indicated (n = 4–8).(A) is representative of two or more independent experiments; (B)–(E) present data pooled from three or more experiments. Statistical significance in (C) was determined using the Holm-Sidak method.All error bars represent mean ± SD. See also Figure S5.
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fig5: Villin-Specific Btnl1 Induction Rescues Vγ7+ IEL In Vivo(A–D) Week 7–13 (adult) or day 7–21 (pups) mice of indicated genotypes on a Btnl1−/− background were administered Dox (1 mg/ml, 2% sucrose) or control water (2% sucrose) for times indicated, and IELs were analyzed by flow cytometry. n ≥ 5 (A and B); n ≥ 6 (C and D).(E) Comparative cell-surface phenotypes of Vγ7+ IELs from week 4–5 WT mice and animals indicated (n = 4–8).(A) is representative of two or more independent experiments; (B)–(E) present data pooled from three or more experiments. Statistical significance in (C) was determined using the Holm-Sidak method.All error bars represent mean ± SD. See also Figure S5.

Mentions: In further experiments, we restricted Btnl1 induction to mature enterocytes by generating Btnl1−/− mice transgenic for rtTA expressed from the villin promoter. Within 1–2 weeks of Dox-treatment of several W11 BiTg Btnl1−/− mice, most Vγ7+ IELs had become Lag3hi, Thy1−, and CD122hi, of which the majority were also Ki67+ (Figures 5A and 5B). Again, this phenotypic transition was Vγ7+ IEL specific, albeit there were sometimes Btnl1-independent increases in Ki67+ TCRβ+ IELs in sugar-water-treated mice. (Figure 5B). Once more, the numbers and representation of Vγ7+ IELs were unchanged, even in mice retained on Dox for 3–4 weeks (Figure 5C). This establishes that Btnl1 can effect phenotypic conversion of immature Vγ7+ IELs rather than merely promote a selective outgrowth of mature Vγ7+ cells.


Epithelia Use Butyrophilin-like Molecules to Shape Organ-Specific γ δ T Cell Compartments
Villin-Specific Btnl1 Induction Rescues Vγ7+ IEL In Vivo(A–D) Week 7–13 (adult) or day 7–21 (pups) mice of indicated genotypes on a Btnl1−/− background were administered Dox (1 mg/ml, 2% sucrose) or control water (2% sucrose) for times indicated, and IELs were analyzed by flow cytometry. n ≥ 5 (A and B); n ≥ 6 (C and D).(E) Comparative cell-surface phenotypes of Vγ7+ IELs from week 4–5 WT mice and animals indicated (n = 4–8).(A) is representative of two or more independent experiments; (B)–(E) present data pooled from three or more experiments. Statistical significance in (C) was determined using the Holm-Sidak method.All error bars represent mean ± SD. See also Figure S5.
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Related In: Results  -  Collection

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fig5: Villin-Specific Btnl1 Induction Rescues Vγ7+ IEL In Vivo(A–D) Week 7–13 (adult) or day 7–21 (pups) mice of indicated genotypes on a Btnl1−/− background were administered Dox (1 mg/ml, 2% sucrose) or control water (2% sucrose) for times indicated, and IELs were analyzed by flow cytometry. n ≥ 5 (A and B); n ≥ 6 (C and D).(E) Comparative cell-surface phenotypes of Vγ7+ IELs from week 4–5 WT mice and animals indicated (n = 4–8).(A) is representative of two or more independent experiments; (B)–(E) present data pooled from three or more experiments. Statistical significance in (C) was determined using the Holm-Sidak method.All error bars represent mean ± SD. See also Figure S5.
Mentions: In further experiments, we restricted Btnl1 induction to mature enterocytes by generating Btnl1−/− mice transgenic for rtTA expressed from the villin promoter. Within 1–2 weeks of Dox-treatment of several W11 BiTg Btnl1−/− mice, most Vγ7+ IELs had become Lag3hi, Thy1−, and CD122hi, of which the majority were also Ki67+ (Figures 5A and 5B). Again, this phenotypic transition was Vγ7+ IEL specific, albeit there were sometimes Btnl1-independent increases in Ki67+ TCRβ+ IELs in sugar-water-treated mice. (Figure 5B). Once more, the numbers and representation of Vγ7+ IELs were unchanged, even in mice retained on Dox for 3–4 weeks (Figure 5C). This establishes that Btnl1 can effect phenotypic conversion of immature Vγ7+ IELs rather than merely promote a selective outgrowth of mature Vγ7+ cells.

View Article: PubMed Central - PubMed

ABSTRACT

Many body surfaces harbor organ-specific γδ T cell compartments that contribute to tissue integrity. Thus, murine dendritic epidermal T cells (DETCs) uniquely expressing T cell receptor (TCR)-Vγ5 chains protect from cutaneous carcinogens. The DETC repertoire is shaped by Skint1, a butyrophilin-like (Btnl) gene expressed specifically by thymic epithelial cells and suprabasal keratinocytes. However, the generality of this mechanism has remained opaque, since neither Skint1 nor DETCs are evolutionarily conserved. Here, Btnl1 expressed by murine enterocytes is shown to shape the local TCR-Vγ7+ γδ compartment. Uninfluenced by microbial or food antigens, this activity evokes the developmental selection of TCRαβ+ repertoires. Indeed, Btnl1 and Btnl6 jointly induce TCR-dependent responses specifically in intestinal Vγ7+ cells. Likewise, human gut epithelial cells express BTNL3 and BTNL8 that jointly induce selective TCR-dependent responses of human colonic Vγ4+ cells. Hence, a conserved mechanism emerges whereby epithelia use organ-specific BTNL/Btnl genes to shape local T cell compartments.

No MeSH data available.


Related in: MedlinePlus