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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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A Gut IEL Selecting Element(A) Left: IEL composition in WT versus NU/NU mice; antibody GL2 detects TRDV2-2-encoded Vδ4 chain. Right: surface CD122 expression on NU/NU Vγ7+ IELs (n ≥ 12).(B) IEL composition (top), enumeration (bottom left), and CD122 expression (bottom right) in germ-free (GF), food antigen-free (FAF), or GF-FAF C57Bl/6 mice at weeks 9–13 (n ≥ 4).(C) qRT-PCR of denoted genes.(D) Histological analysis of Btnl1 RNA (middle: RNAScope) and 3-hr BrdU incorporation in vivo (bottom) in paraffin-embedded SI gut rolls (n ≥ 3).(E) RNAScope of Btnl1, Btnl4, and Btnl6 in WT versus Btnl1−/− and Btnl4−/− mice.Data are representative of two (B), two or more (D and E), or three or more (A) independent experiments. In (C), data are pooled from two independent experiments.All error bars represent mean ± SD. See also Figure S2.
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fig2: A Gut IEL Selecting Element(A) Left: IEL composition in WT versus NU/NU mice; antibody GL2 detects TRDV2-2-encoded Vδ4 chain. Right: surface CD122 expression on NU/NU Vγ7+ IELs (n ≥ 12).(B) IEL composition (top), enumeration (bottom left), and CD122 expression (bottom right) in germ-free (GF), food antigen-free (FAF), or GF-FAF C57Bl/6 mice at weeks 9–13 (n ≥ 4).(C) qRT-PCR of denoted genes.(D) Histological analysis of Btnl1 RNA (middle: RNAScope) and 3-hr BrdU incorporation in vivo (bottom) in paraffin-embedded SI gut rolls (n ≥ 3).(E) RNAScope of Btnl1, Btnl4, and Btnl6 in WT versus Btnl1−/− and Btnl4−/− mice.Data are representative of two (B), two or more (D and E), or three or more (A) independent experiments. In (C), data are pooled from two independent experiments.All error bars represent mean ± SD. See also Figure S2.

Mentions: Because Skint1 selects for signature Vγ5+ DETC progenitors in the thymus, DETCs are absent from athymic NU/NU mice. By contrast, intestinal IELs were present in NU/NU, and although there was some decrease in numbers (average of ∼1.3 × 106 cells compared to >2.0 × 106 cells in euthymic mice; see below), the compartment was again dominated by CD122hi Vγ7+ IELs. Moreover, ∼25% of Vγ7+ IELs in NU/NU and in euthymic mice reacted with antibody GL2 that detects Vδ4 (TRDV2-2 encoded) chains. Consistent with this, TRDV2-2 sequences accounted for ∼25% of TCRδ chain RNAs expressed by purified Vγ7+ IELs (Figures 2A and S2A). In sum, the shaping of the gut Vγ7+ IEL compartment did not require a thymus.


Epithelia Use Butyrophilin-like Molecules to Shape Organ-Specific γ δ T Cell Compartments
A Gut IEL Selecting Element(A) Left: IEL composition in WT versus NU/NU mice; antibody GL2 detects TRDV2-2-encoded Vδ4 chain. Right: surface CD122 expression on NU/NU Vγ7+ IELs (n ≥ 12).(B) IEL composition (top), enumeration (bottom left), and CD122 expression (bottom right) in germ-free (GF), food antigen-free (FAF), or GF-FAF C57Bl/6 mice at weeks 9–13 (n ≥ 4).(C) qRT-PCR of denoted genes.(D) Histological analysis of Btnl1 RNA (middle: RNAScope) and 3-hr BrdU incorporation in vivo (bottom) in paraffin-embedded SI gut rolls (n ≥ 3).(E) RNAScope of Btnl1, Btnl4, and Btnl6 in WT versus Btnl1−/− and Btnl4−/− mice.Data are representative of two (B), two or more (D and E), or three or more (A) independent experiments. In (C), data are pooled from two independent experiments.All error bars represent mean ± SD. See also Figure S2.
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fig2: A Gut IEL Selecting Element(A) Left: IEL composition in WT versus NU/NU mice; antibody GL2 detects TRDV2-2-encoded Vδ4 chain. Right: surface CD122 expression on NU/NU Vγ7+ IELs (n ≥ 12).(B) IEL composition (top), enumeration (bottom left), and CD122 expression (bottom right) in germ-free (GF), food antigen-free (FAF), or GF-FAF C57Bl/6 mice at weeks 9–13 (n ≥ 4).(C) qRT-PCR of denoted genes.(D) Histological analysis of Btnl1 RNA (middle: RNAScope) and 3-hr BrdU incorporation in vivo (bottom) in paraffin-embedded SI gut rolls (n ≥ 3).(E) RNAScope of Btnl1, Btnl4, and Btnl6 in WT versus Btnl1−/− and Btnl4−/− mice.Data are representative of two (B), two or more (D and E), or three or more (A) independent experiments. In (C), data are pooled from two independent experiments.All error bars represent mean ± SD. See also Figure S2.
Mentions: Because Skint1 selects for signature Vγ5+ DETC progenitors in the thymus, DETCs are absent from athymic NU/NU mice. By contrast, intestinal IELs were present in NU/NU, and although there was some decrease in numbers (average of ∼1.3 × 106 cells compared to >2.0 × 106 cells in euthymic mice; see below), the compartment was again dominated by CD122hi Vγ7+ IELs. Moreover, ∼25% of Vγ7+ IELs in NU/NU and in euthymic mice reacted with antibody GL2 that detects Vδ4 (TRDV2-2 encoded) chains. Consistent with this, TRDV2-2 sequences accounted for ∼25% of TCRδ chain RNAs expressed by purified Vγ7+ IELs (Figures 2A and S2A). In sum, the shaping of the gut Vγ7+ IEL compartment did not require a thymus.

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