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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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Btnl1 Drives Selective Expansion and Maturation of Gut IEL(A) 3 hr EdU incorporation in vivo in γδ IEL subsets and thymocytes from week 4 WT versus Btnl1−/− mice (n ≥ 9). (B) Surface phenotypes of Vγ7+ and Vγ7GL2+ IELs from week 3–5 WT and Btnl1−/− mice (n ≥ 8).(C) Top: Thy1 and CD122 expression by Vγ7+ IEL from day 35 Btnl1−/− mice (n = 8). Bottom: surface phenotypes of CD122HIThy1− and CD122LOThy1+ Vγ7+ IELs from week 4–6 Btnl1−/− mice (n ≥ 4). W, week.(D and E) IEL reconstitution and CD122 profiles in (D) irradiated TCRδ−/− mice 9–10 weeks post-BM transfers from indicated donors (n ≥ 7) and (E) irradiated CD45.2+ WT or Btnl1−/− mice 4–5 weeks post-BM transfers from CD45.1+ C57Bl/6 mice (n = 7).Data are representative of two (D and E) or three or more (C, top) independent experiments. Panels (A) and (C) (bottom) present data pooled from three or more experiments.All error bars represent mean ± SD. See also Figure S4.
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fig4: Btnl1 Drives Selective Expansion and Maturation of Gut IEL(A) 3 hr EdU incorporation in vivo in γδ IEL subsets and thymocytes from week 4 WT versus Btnl1−/− mice (n ≥ 9). (B) Surface phenotypes of Vγ7+ and Vγ7GL2+ IELs from week 3–5 WT and Btnl1−/− mice (n ≥ 8).(C) Top: Thy1 and CD122 expression by Vγ7+ IEL from day 35 Btnl1−/− mice (n = 8). Bottom: surface phenotypes of CD122HIThy1− and CD122LOThy1+ Vγ7+ IELs from week 4–6 Btnl1−/− mice (n ≥ 4). W, week.(D and E) IEL reconstitution and CD122 profiles in (D) irradiated TCRδ−/− mice 9–10 weeks post-BM transfers from indicated donors (n ≥ 7) and (E) irradiated CD45.2+ WT or Btnl1−/− mice 4–5 weeks post-BM transfers from CD45.1+ C57Bl/6 mice (n = 7).Data are representative of two (D and E) or three or more (C, top) independent experiments. Panels (A) and (C) (bottom) present data pooled from three or more experiments.All error bars represent mean ± SD. See also Figure S4.

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
Btnl1 Drives Selective Expansion and Maturation of Gut IEL(A) 3 hr EdU incorporation in vivo in γδ IEL subsets and thymocytes from week 4 WT versus Btnl1−/− mice (n ≥ 9). (B) Surface phenotypes of Vγ7+ and Vγ7GL2+ IELs from week 3–5 WT and Btnl1−/− mice (n ≥ 8).(C) Top: Thy1 and CD122 expression by Vγ7+ IEL from day 35 Btnl1−/− mice (n = 8). Bottom: surface phenotypes of CD122HIThy1− and CD122LOThy1+ Vγ7+ IELs from week 4–6 Btnl1−/− mice (n ≥ 4). W, week.(D and E) IEL reconstitution and CD122 profiles in (D) irradiated TCRδ−/− mice 9–10 weeks post-BM transfers from indicated donors (n ≥ 7) and (E) irradiated CD45.2+ WT or Btnl1−/− mice 4–5 weeks post-BM transfers from CD45.1+ C57Bl/6 mice (n = 7).Data are representative of two (D and E) or three or more (C, top) independent experiments. Panels (A) and (C) (bottom) present data pooled from three or more experiments.All error bars represent mean ± SD. See also Figure S4.
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fig4: Btnl1 Drives Selective Expansion and Maturation of Gut IEL(A) 3 hr EdU incorporation in vivo in γδ IEL subsets and thymocytes from week 4 WT versus Btnl1−/− mice (n ≥ 9). (B) Surface phenotypes of Vγ7+ and Vγ7GL2+ IELs from week 3–5 WT and Btnl1−/− mice (n ≥ 8).(C) Top: Thy1 and CD122 expression by Vγ7+ IEL from day 35 Btnl1−/− mice (n = 8). Bottom: surface phenotypes of CD122HIThy1− and CD122LOThy1+ Vγ7+ IELs from week 4–6 Btnl1−/− mice (n ≥ 4). W, week.(D and E) IEL reconstitution and CD122 profiles in (D) irradiated TCRδ−/− mice 9–10 weeks post-BM transfers from indicated donors (n ≥ 7) and (E) irradiated CD45.2+ WT or Btnl1−/− mice 4–5 weeks post-BM transfers from CD45.1+ C57Bl/6 mice (n = 7).Data are representative of two (D and E) or three or more (C, top) independent experiments. Panels (A) and (C) (bottom) present data pooled from three or more experiments.All error bars represent mean ± SD. See also Figure S4.
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