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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.

No MeSH data available.


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Impact of Btnl1 on Intestinal Engraftment, Expansion, and Retention of CD122HI Vγ7+ IELs, Related to Figure 4(A) Ki67+ expression in Vγ7+ IEL isolated from WT versus Btnl1−/− mice (n = 4-27). (B) Cell surface phenotype of Btnl1−/− Vγ7+CD122HI versus Vγ7+CD122LO and Vγ7+GL2+CD122HI versus Vγ7+GL2+CD122LO IEL displayed in Figure 4B (n ≥ 8). (C) Irradiated TCRδ KO mice reconstituted with WT bone marrow (BM) were analyzed for γδ IEL composition at the indicated time-points after BM transfer (n ≥ 3). (D) IEL isolated from WT W4-5 mice were column-purified using CD45 microbeads and adoptively transferred intravenously into W6 TCRδ−/− or TCRδ−/−Btnl1−/− hosts. γδ T cell composition was assayed 2-3 weeks later by flow cytometry (n ≥ 5). Data are representative of 1 (C), 2 (D) or ≥ 3 (B) independent experiments. Bar graph displays mean ± SD. All error bars represent mean ± SD.
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figs4: Impact of Btnl1 on Intestinal Engraftment, Expansion, and Retention of CD122HI Vγ7+ IELs, Related to Figure 4(A) Ki67+ expression in Vγ7+ IEL isolated from WT versus Btnl1−/− mice (n = 4-27). (B) Cell surface phenotype of Btnl1−/− Vγ7+CD122HI versus Vγ7+CD122LO and Vγ7+GL2+CD122HI versus Vγ7+GL2+CD122LO IEL displayed in Figure 4B (n ≥ 8). (C) Irradiated TCRδ KO mice reconstituted with WT bone marrow (BM) were analyzed for γδ IEL composition at the indicated time-points after BM transfer (n ≥ 3). (D) IEL isolated from WT W4-5 mice were column-purified using CD45 microbeads and adoptively transferred intravenously into W6 TCRδ−/− or TCRδ−/−Btnl1−/− hosts. γδ T cell composition was assayed 2-3 weeks later by flow cytometry (n ≥ 5). Data are representative of 1 (C), 2 (D) or ≥ 3 (B) independent experiments. Bar graph displays mean ± SD. All error bars represent mean ± SD.

Mentions: To determine how and when Btnl1 impacts IELs, we examined residual Vγ7+ and Vγ7GL2+ IELs in Btnl1−/− mice. Relative to those in WT mice, significantly fewer Vγ7+ IELs incorporated EdU at D28 [p < 0.0001] or expressed Ki67, and this did not change until W7 when most Vγ7+ IELs in WT mice moved out of cycling (Figures 4A and S4A). Thus, there was no selective expansion of Vγ7+ IELs in Btnl1−/− mice. Similarly, although their TCR levels were high, many residual Vγ7+ and Vγ7GL2+ IELs in week 3–5 Btnl1−/− mice were CD122lo, Thy1+, TIGIT−, Lag3−, CD8αα−, CD5+, CD24+, thereby phenocopying immature Vγ7+ IELs of day 14–17 WT mice (Figures 4B, 4C, and S4B).


Epithelia Use Butyrophilin-like Molecules to Shape Organ-Specific γ δ T Cell Compartments
Impact of Btnl1 on Intestinal Engraftment, Expansion, and Retention of CD122HI Vγ7+ IELs, Related to Figure 4(A) Ki67+ expression in Vγ7+ IEL isolated from WT versus Btnl1−/− mice (n = 4-27). (B) Cell surface phenotype of Btnl1−/− Vγ7+CD122HI versus Vγ7+CD122LO and Vγ7+GL2+CD122HI versus Vγ7+GL2+CD122LO IEL displayed in Figure 4B (n ≥ 8). (C) Irradiated TCRδ KO mice reconstituted with WT bone marrow (BM) were analyzed for γδ IEL composition at the indicated time-points after BM transfer (n ≥ 3). (D) IEL isolated from WT W4-5 mice were column-purified using CD45 microbeads and adoptively transferred intravenously into W6 TCRδ−/− or TCRδ−/−Btnl1−/− hosts. γδ T cell composition was assayed 2-3 weeks later by flow cytometry (n ≥ 5). Data are representative of 1 (C), 2 (D) or ≥ 3 (B) independent experiments. Bar graph displays mean ± SD. All error bars represent mean ± SD.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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Show All Figures
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figs4: Impact of Btnl1 on Intestinal Engraftment, Expansion, and Retention of CD122HI Vγ7+ IELs, Related to Figure 4(A) Ki67+ expression in Vγ7+ IEL isolated from WT versus Btnl1−/− mice (n = 4-27). (B) Cell surface phenotype of Btnl1−/− Vγ7+CD122HI versus Vγ7+CD122LO and Vγ7+GL2+CD122HI versus Vγ7+GL2+CD122LO IEL displayed in Figure 4B (n ≥ 8). (C) Irradiated TCRδ KO mice reconstituted with WT bone marrow (BM) were analyzed for γδ IEL composition at the indicated time-points after BM transfer (n ≥ 3). (D) IEL isolated from WT W4-5 mice were column-purified using CD45 microbeads and adoptively transferred intravenously into W6 TCRδ−/− or TCRδ−/−Btnl1−/− hosts. γδ T cell composition was assayed 2-3 weeks later by flow cytometry (n ≥ 5). Data are representative of 1 (C), 2 (D) or ≥ 3 (B) independent experiments. Bar graph displays mean ± SD. All error bars represent mean ± SD.
Mentions: To determine how and when Btnl1 impacts IELs, we examined residual Vγ7+ and Vγ7GL2+ IELs in Btnl1−/− mice. Relative to those in WT mice, significantly fewer Vγ7+ IELs incorporated EdU at D28 [p < 0.0001] or expressed Ki67, and this did not change until W7 when most Vγ7+ IELs in WT mice moved out of cycling (Figures 4A and S4A). Thus, there was no selective expansion of Vγ7+ IELs in Btnl1−/− mice. Similarly, although their TCR levels were high, many residual Vγ7+ and Vγ7GL2+ IELs in week 3–5 Btnl1−/− mice were CD122lo, Thy1+, TIGIT−, Lag3−, CD8αα−, CD5+, CD24+, thereby phenocopying immature Vγ7+ IELs of day 14–17 WT mice (Figures 4B, 4C, and S4B).

View Article: PubMed Central - PubMed

ABSTRACT

Many body surfaces harbor organ-specific &gamma;&delta; T&nbsp;cell compartments that contribute to tissue integrity. Thus, murine dendritic epidermal T&nbsp;cells (DETCs) uniquely expressing T&nbsp;cell receptor (TCR)-V&gamma;5 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-V&gamma;7+ &gamma;&delta; compartment. Uninfluenced by microbial or food antigens, this activity evokes the developmental selection of TCR&alpha;&beta;+ repertoires. Indeed, Btnl1 and Btnl6 jointly induce TCR-dependent responses specifically in intestinal V&gamma;7+ cells. Likewise, human gut epithelial cells express BTNL3 and BTNL8 that jointly induce selective TCR-dependent responses of human colonic V&gamma;4+ cells. Hence, a conserved mechanism emerges whereby epithelia use organ-specific BTNL/Btnl genes to shape local T&nbsp;cell compartments.

No MeSH data available.


Related in: MedlinePlus