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Mucosal memory CD8⁺ T cells are selected in the periphery by an MHC class I molecule.

Huang Y, Park Y, Wang-Zhu Y, Larange A, Arens R, Bernardo I, Olivares-Villagómez D, Herndler-Brandstetter D, Abraham N, Grubeck-Loebenstein B, Schoenberger SP, Van Kaer L, Kronenberg M, Teitell MA, Cheroutre H - Nat. Immunol. (2011)

Bottom Line: The presence of immune memory at pathogen-entry sites is a prerequisite for protection.Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood.Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αβ(+) memory T cells.

View Article: PubMed Central - PubMed

Affiliation: Division of Developmental Immunology, La Jolla Institute for Allergy & Immunology, La Jolla, California, USA.

ABSTRACT
The presence of immune memory at pathogen-entry sites is a prerequisite for protection. Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood. Here we show that the nonclassical major histocompatibility complex (MHC) class I molecule thymus leukemia antigen (TL), induced on dendritic cells interacting with CD8αα on activated CD8αβ(+) T cells, mediated affinity-based selection of memory precursor cells. Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αβ(+) memory T cells. The memory process driven by TL and CD8αα was essential for the generation of CD8αβ(+) memory T cells in the intestine and the accumulation of highly antigen-sensitive CD8αβ(+) memory T cells that form the first line of defense at the largest entry port for pathogens.

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Retinoic acid promotes the affinity-based accumulation of CD8αα+ CD8αβ T cells in the intestine(a) OT-I cells were stimulated by OVAp-loaded DCs from SPL or mLN of WT mice with or without 100 nM RA (dot plots) or with LE135 (histogram) in vitro for 3 d and CD8αα expression was analyzed. Data are representative of five independent experiments. (b,c) OT-I cells were stimulated by SPL or mLN DCs pulsed with OVAp (high, 1 nM; low, 0.01 nM) in the presence or absence of 100 nM RA (b) or 5 ng/ml TGF-β (c) in vitro for 3 d and CD8αα expression was analyzed. Data are representative of more than five independent experiments. (d,e) 0.5 × 106 CD8+ OT-I cells isolated from naïve Ly5.1+ OT-I+ Rag-/- mice were adoptively transferred into B6 recipient mice. 1 d after transfer, mice were orally infected by 0.5 × 109 ActA- Lm-OVA. CD8αα expression was measured on gated donor OT-I cells from the SPL, mLN, PP and IEL, 5 d p.i. (d). CD8αα and CD103 expression is shown on gated donor OT-I cells from the spleen and IEL on days 12, 21 and 75 p.i. (e). Representative data from two to three mice per group are shown. At least three independent experiments were performed.
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Figure 6: Retinoic acid promotes the affinity-based accumulation of CD8αα+ CD8αβ T cells in the intestine(a) OT-I cells were stimulated by OVAp-loaded DCs from SPL or mLN of WT mice with or without 100 nM RA (dot plots) or with LE135 (histogram) in vitro for 3 d and CD8αα expression was analyzed. Data are representative of five independent experiments. (b,c) OT-I cells were stimulated by SPL or mLN DCs pulsed with OVAp (high, 1 nM; low, 0.01 nM) in the presence or absence of 100 nM RA (b) or 5 ng/ml TGF-β (c) in vitro for 3 d and CD8αα expression was analyzed. Data are representative of more than five independent experiments. (d,e) 0.5 × 106 CD8+ OT-I cells isolated from naïve Ly5.1+ OT-I+ Rag-/- mice were adoptively transferred into B6 recipient mice. 1 d after transfer, mice were orally infected by 0.5 × 109 ActA- Lm-OVA. CD8αα expression was measured on gated donor OT-I cells from the SPL, mLN, PP and IEL, 5 d p.i. (d). CD8αα and CD103 expression is shown on gated donor OT-I cells from the spleen and IEL on days 12, 21 and 75 p.i. (e). Representative data from two to three mice per group are shown. At least three independent experiments were performed.

Mentions: CD8αα-expressing CD8αβ T cells are highly enriched in the epithelium of the intestine, suggesting that a selective process based on CD8αα expression might drive this localized accumulation. Consistent with this notion, when primed in vitro CD8αα induction was stronger using mLN DCs compared to splenic DCs (Fig. 6a,b). In the presence of exogenous RA, normally released by mLN DCs during priming21, splenic DCs also mediated strong induction of CD8αα on the OT-I T cells they primed (Fig. 6a,b). Conversely, a retinoic acid receptor (RAR) inhibitor reduced CD8αα expression on T cells primed by mLN DCs (Fig. 6a). Likewise, TGF-β known to be an important modulator of mucosal T cell differentiation also increased CD8αα induction on activated CD8αβ primary effector cells (Fig. 6c). Both, RA- and TGF-β-mediated enhanced induction of CD8αα were observed, however, only under strong antigen activation conditions, suggesting that they influence CD8 effector differentiation by further promoting the selective marking of high-affinity effector cells by CD8αα (Fig. 6b, c).


Mucosal memory CD8⁺ T cells are selected in the periphery by an MHC class I molecule.

Huang Y, Park Y, Wang-Zhu Y, Larange A, Arens R, Bernardo I, Olivares-Villagómez D, Herndler-Brandstetter D, Abraham N, Grubeck-Loebenstein B, Schoenberger SP, Van Kaer L, Kronenberg M, Teitell MA, Cheroutre H - Nat. Immunol. (2011)

Retinoic acid promotes the affinity-based accumulation of CD8αα+ CD8αβ T cells in the intestine(a) OT-I cells were stimulated by OVAp-loaded DCs from SPL or mLN of WT mice with or without 100 nM RA (dot plots) or with LE135 (histogram) in vitro for 3 d and CD8αα expression was analyzed. Data are representative of five independent experiments. (b,c) OT-I cells were stimulated by SPL or mLN DCs pulsed with OVAp (high, 1 nM; low, 0.01 nM) in the presence or absence of 100 nM RA (b) or 5 ng/ml TGF-β (c) in vitro for 3 d and CD8αα expression was analyzed. Data are representative of more than five independent experiments. (d,e) 0.5 × 106 CD8+ OT-I cells isolated from naïve Ly5.1+ OT-I+ Rag-/- mice were adoptively transferred into B6 recipient mice. 1 d after transfer, mice were orally infected by 0.5 × 109 ActA- Lm-OVA. CD8αα expression was measured on gated donor OT-I cells from the SPL, mLN, PP and IEL, 5 d p.i. (d). CD8αα and CD103 expression is shown on gated donor OT-I cells from the spleen and IEL on days 12, 21 and 75 p.i. (e). Representative data from two to three mice per group are shown. At least three independent experiments were performed.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3197978&req=5

Figure 6: Retinoic acid promotes the affinity-based accumulation of CD8αα+ CD8αβ T cells in the intestine(a) OT-I cells were stimulated by OVAp-loaded DCs from SPL or mLN of WT mice with or without 100 nM RA (dot plots) or with LE135 (histogram) in vitro for 3 d and CD8αα expression was analyzed. Data are representative of five independent experiments. (b,c) OT-I cells were stimulated by SPL or mLN DCs pulsed with OVAp (high, 1 nM; low, 0.01 nM) in the presence or absence of 100 nM RA (b) or 5 ng/ml TGF-β (c) in vitro for 3 d and CD8αα expression was analyzed. Data are representative of more than five independent experiments. (d,e) 0.5 × 106 CD8+ OT-I cells isolated from naïve Ly5.1+ OT-I+ Rag-/- mice were adoptively transferred into B6 recipient mice. 1 d after transfer, mice were orally infected by 0.5 × 109 ActA- Lm-OVA. CD8αα expression was measured on gated donor OT-I cells from the SPL, mLN, PP and IEL, 5 d p.i. (d). CD8αα and CD103 expression is shown on gated donor OT-I cells from the spleen and IEL on days 12, 21 and 75 p.i. (e). Representative data from two to three mice per group are shown. At least three independent experiments were performed.
Mentions: CD8αα-expressing CD8αβ T cells are highly enriched in the epithelium of the intestine, suggesting that a selective process based on CD8αα expression might drive this localized accumulation. Consistent with this notion, when primed in vitro CD8αα induction was stronger using mLN DCs compared to splenic DCs (Fig. 6a,b). In the presence of exogenous RA, normally released by mLN DCs during priming21, splenic DCs also mediated strong induction of CD8αα on the OT-I T cells they primed (Fig. 6a,b). Conversely, a retinoic acid receptor (RAR) inhibitor reduced CD8αα expression on T cells primed by mLN DCs (Fig. 6a). Likewise, TGF-β known to be an important modulator of mucosal T cell differentiation also increased CD8αα induction on activated CD8αβ primary effector cells (Fig. 6c). Both, RA- and TGF-β-mediated enhanced induction of CD8αα were observed, however, only under strong antigen activation conditions, suggesting that they influence CD8 effector differentiation by further promoting the selective marking of high-affinity effector cells by CD8αα (Fig. 6b, c).

Bottom Line: The presence of immune memory at pathogen-entry sites is a prerequisite for protection.Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood.Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αβ(+) memory T cells.

View Article: PubMed Central - PubMed

Affiliation: Division of Developmental Immunology, La Jolla Institute for Allergy & Immunology, La Jolla, California, USA.

ABSTRACT
The presence of immune memory at pathogen-entry sites is a prerequisite for protection. Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood. Here we show that the nonclassical major histocompatibility complex (MHC) class I molecule thymus leukemia antigen (TL), induced on dendritic cells interacting with CD8αα on activated CD8αβ(+) T cells, mediated affinity-based selection of memory precursor cells. Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αβ(+) memory T cells. The memory process driven by TL and CD8αα was essential for the generation of CD8αβ(+) memory T cells in the intestine and the accumulation of highly antigen-sensitive CD8αβ(+) memory T cells that form the first line of defense at the largest entry port for pathogens.

Show MeSH
Related in: MedlinePlus