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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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Btnl1 Has No Detectable Effect on the Systemic T, B, and Myeloid Cell Compartments, Related to Figure 3(A) γδ IEL composition in adult WT versus Btnl1indel/indel mice (n = 3) (B) Mesenteric Lymph Node (MLN) and (C) Splenic immune compartments of WT, Btnl1+/− and Btnl1−/− analyzed by flow cytometry (n = 7–9). (D) TCRVγ chain usage in MLN and splenic lymphocytes harvested from WT, Btnl1+/− and Btnl1−/− mice assessed by flow cytometry (n = 8). (E) Vγ7+ and Vγ7+GL2+ thymocytes from WT or Btnl1+/− and Btnl1−/− mice assayed by flow cytometry to enumerate total cell counts (left) and cell surface phenotype (right) at three time points. Panels (A-D) are representative of 1 experiment. Panel E-left presents data pooled from ≥ 2 independent experiments. All error bars represent mean ± SD. See Table S3.
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figs3: Btnl1 Has No Detectable Effect on the Systemic T, B, and Myeloid Cell Compartments, Related to Figure 3(A) γδ IEL composition in adult WT versus Btnl1indel/indel mice (n = 3) (B) Mesenteric Lymph Node (MLN) and (C) Splenic immune compartments of WT, Btnl1+/− and Btnl1−/− analyzed by flow cytometry (n = 7–9). (D) TCRVγ chain usage in MLN and splenic lymphocytes harvested from WT, Btnl1+/− and Btnl1−/− mice assessed by flow cytometry (n = 8). (E) Vγ7+ and Vγ7+GL2+ thymocytes from WT or Btnl1+/− and Btnl1−/− mice assayed by flow cytometry to enumerate total cell counts (left) and cell surface phenotype (right) at three time points. Panels (A-D) are representative of 1 experiment. Panel E-left presents data pooled from ≥ 2 independent experiments. All error bars represent mean ± SD. See Table S3.

Mentions: The four Btnl1−/− strains each displayed major, highly selective losses of Vγ7+ IELs, assessed by flow cytometry or confocal microscopy (Figures 3A, 3B, and S3A). Vγ7+ IEL numbers were depleted by ∼90%, with Vγ7GL2+ cells almost ablated. Because Vγ7− IEL numbers barely increased, the percentage representation of Vγ7+ cells among γδ IELs was reduced only by ∼3-fold relative to wild-type (WT) mice, but this was set against a background of dramatically reduced γδ IEL numbers (Figures 3A and S3A). By contrast, TCRβ+CD8αα+ IEL numbers increased significantly in Btnl1−/− mice (Figures 3A and 3B).


Epithelia Use Butyrophilin-like Molecules to Shape Organ-Specific γ δ T Cell Compartments
Btnl1 Has No Detectable Effect on the Systemic T, B, and Myeloid Cell Compartments, Related to Figure 3(A) γδ IEL composition in adult WT versus Btnl1indel/indel mice (n = 3) (B) Mesenteric Lymph Node (MLN) and (C) Splenic immune compartments of WT, Btnl1+/− and Btnl1−/− analyzed by flow cytometry (n = 7–9). (D) TCRVγ chain usage in MLN and splenic lymphocytes harvested from WT, Btnl1+/− and Btnl1−/− mice assessed by flow cytometry (n = 8). (E) Vγ7+ and Vγ7+GL2+ thymocytes from WT or Btnl1+/− and Btnl1−/− mice assayed by flow cytometry to enumerate total cell counts (left) and cell surface phenotype (right) at three time points. Panels (A-D) are representative of 1 experiment. Panel E-left presents data pooled from ≥ 2 independent experiments. All error bars represent mean ± SD. See Table S3.
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Related In: Results  -  Collection

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figs3: Btnl1 Has No Detectable Effect on the Systemic T, B, and Myeloid Cell Compartments, Related to Figure 3(A) γδ IEL composition in adult WT versus Btnl1indel/indel mice (n = 3) (B) Mesenteric Lymph Node (MLN) and (C) Splenic immune compartments of WT, Btnl1+/− and Btnl1−/− analyzed by flow cytometry (n = 7–9). (D) TCRVγ chain usage in MLN and splenic lymphocytes harvested from WT, Btnl1+/− and Btnl1−/− mice assessed by flow cytometry (n = 8). (E) Vγ7+ and Vγ7+GL2+ thymocytes from WT or Btnl1+/− and Btnl1−/− mice assayed by flow cytometry to enumerate total cell counts (left) and cell surface phenotype (right) at three time points. Panels (A-D) are representative of 1 experiment. Panel E-left presents data pooled from ≥ 2 independent experiments. All error bars represent mean ± SD. See Table S3.
Mentions: The four Btnl1−/− strains each displayed major, highly selective losses of Vγ7+ IELs, assessed by flow cytometry or confocal microscopy (Figures 3A, 3B, and S3A). Vγ7+ IEL numbers were depleted by ∼90%, with Vγ7GL2+ cells almost ablated. Because Vγ7− IEL numbers barely increased, the percentage representation of Vγ7+ cells among γδ IELs was reduced only by ∼3-fold relative to wild-type (WT) mice, but this was set against a background of dramatically reduced γδ IEL numbers (Figures 3A and S3A). By contrast, TCRβ+CD8αα+ IEL numbers increased significantly in Btnl1−/− mice (Figures 3A and 3B).

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