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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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Activation-induced CD8αα rescues CD8αβ primary effector T cells from TICD(a) 2 × 105 CFSE-labeled naïve ΔE8I OT-I cells were cultured with 4 × 104 OVAp-pulsed DCs from SPL or mLN of WT or TL- mice that were previously orally infected with ActA- Lm-OVA. After 2 d culture, OT-I cells were harvested and analyzed for cell death by Annexin V staining. (b) 5 × 104 naïve Ly5.2+ WT or Ly5.2+ ΔE8I OT-I cells were adoptively transferred into Ly5.1 recipient mice. 1 d after transfer, mice were orally infected with 1 × 109 ActA- Lm-OVA. Donor OT-I cells were tracked in the spleen and IEL, 2 months p.i.. Graph depicts pooled data ± s.e.m.. (c) 5 × 104 naïve Ly5.2+ WT or Ly5.2+ ΔE8I OT-I cells were adoptively transferred into Ly5.1 recipient mice. 1 d after transfer, mice were intravenously infected with 2.5 × 105 ActA- Lm-OVA. Donor OT-I cells were tracked in the spleen and IEL, 2 months p.i.. Graph depicts pooled data ± s.e.m.. (d) As described in (b) and (c), CD8β expression (MFI) was measured on effector WT OT-I or ΔE8I OT-I cells 7 days post oral infection (left) or i.v. infection (right). (e) As described in (c), CD8β expression was measured on memory WT OT-I or ΔE8I OT-I cells 2 m post i.v. infection in the spleen and IEL (f, g) 5 × 104 naïve Ly5.1+Ly5.2+ WT OT-I and 5 × 104 naïve Ly5.2+ ΔE8I OT-I cells were co-transferred into Ly5.1+ WT or Ly5.1+ TL- mice. One day after transfer, the mice were orally infected with 1 × 109 ActA- Lm-OVA. Two months p.i., memory OT-I cells were tracked in the spleen and IEL. (f) Graph depicts pooled data ± s.e.m. (n = 5 per group). (g) Staining for CD8αα expression, using TL-tetramers, on gated memory WT OT-I cells in IEL of WT or TL- recipient mice 2m p.i. * P < 0.001 and ** P < 0.01 (unpaired t-test). Data are representative of three (a, b, c, e, f, g) and two (d) independent experiments.
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Figure 3: Activation-induced CD8αα rescues CD8αβ primary effector T cells from TICD(a) 2 × 105 CFSE-labeled naïve ΔE8I OT-I cells were cultured with 4 × 104 OVAp-pulsed DCs from SPL or mLN of WT or TL- mice that were previously orally infected with ActA- Lm-OVA. After 2 d culture, OT-I cells were harvested and analyzed for cell death by Annexin V staining. (b) 5 × 104 naïve Ly5.2+ WT or Ly5.2+ ΔE8I OT-I cells were adoptively transferred into Ly5.1 recipient mice. 1 d after transfer, mice were orally infected with 1 × 109 ActA- Lm-OVA. Donor OT-I cells were tracked in the spleen and IEL, 2 months p.i.. Graph depicts pooled data ± s.e.m.. (c) 5 × 104 naïve Ly5.2+ WT or Ly5.2+ ΔE8I OT-I cells were adoptively transferred into Ly5.1 recipient mice. 1 d after transfer, mice were intravenously infected with 2.5 × 105 ActA- Lm-OVA. Donor OT-I cells were tracked in the spleen and IEL, 2 months p.i.. Graph depicts pooled data ± s.e.m.. (d) As described in (b) and (c), CD8β expression (MFI) was measured on effector WT OT-I or ΔE8I OT-I cells 7 days post oral infection (left) or i.v. infection (right). (e) As described in (c), CD8β expression was measured on memory WT OT-I or ΔE8I OT-I cells 2 m post i.v. infection in the spleen and IEL (f, g) 5 × 104 naïve Ly5.1+Ly5.2+ WT OT-I and 5 × 104 naïve Ly5.2+ ΔE8I OT-I cells were co-transferred into Ly5.1+ WT or Ly5.1+ TL- mice. One day after transfer, the mice were orally infected with 1 × 109 ActA- Lm-OVA. Two months p.i., memory OT-I cells were tracked in the spleen and IEL. (f) Graph depicts pooled data ± s.e.m. (n = 5 per group). (g) Staining for CD8αα expression, using TL-tetramers, on gated memory WT OT-I cells in IEL of WT or TL- recipient mice 2m p.i. * P < 0.001 and ** P < 0.01 (unpaired t-test). Data are representative of three (a, b, c, e, f, g) and two (d) independent experiments.

Mentions: In contrast to CD8αβ, CD8αα does not function as a TCR co-receptor and similar to TL, CD8αα also does not engage in the TCR activation complex27, 28. However, whereas TL induces death of activated CD8αβ+ T cells, CD8αα, which exhibits a stronger affinity for TL compared to CD8αβ14, promotes the survival of CD8αβ effector cells12, suggesting that activation-induced CD8αα might interfere with TICD. To test this, we compared the survival and memory differentiation of CD8αβ effector T cells in the absence or presence of CD8αα. Due to a deletion of CD8α enhancer region I (Cd8a–E8I)29, OT-I CD8αβ donor cells on the E8I negative background (hereafter called ΔE8I OT-I CD8αβ+T cells do not induce detectable amounts of activation-dependent CD8αα 12. When analyzed in vitro, ΔE8I OT-I CD8αβ+T cells primed by OVA-loaded mLN DCs, which constitutively express TL (Fig. 1e), showed increased activation-induced death compared to their counterparts primed by splenic DCs (Fig. 3a). However, the increase in cell death induced by these mucosal APCs was not observed when mLN and splenic DCs isolated from TL- mice were compared (Fig. 3a).


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)

Activation-induced CD8αα rescues CD8αβ primary effector T cells from TICD(a) 2 × 105 CFSE-labeled naïve ΔE8I OT-I cells were cultured with 4 × 104 OVAp-pulsed DCs from SPL or mLN of WT or TL- mice that were previously orally infected with ActA- Lm-OVA. After 2 d culture, OT-I cells were harvested and analyzed for cell death by Annexin V staining. (b) 5 × 104 naïve Ly5.2+ WT or Ly5.2+ ΔE8I OT-I cells were adoptively transferred into Ly5.1 recipient mice. 1 d after transfer, mice were orally infected with 1 × 109 ActA- Lm-OVA. Donor OT-I cells were tracked in the spleen and IEL, 2 months p.i.. Graph depicts pooled data ± s.e.m.. (c) 5 × 104 naïve Ly5.2+ WT or Ly5.2+ ΔE8I OT-I cells were adoptively transferred into Ly5.1 recipient mice. 1 d after transfer, mice were intravenously infected with 2.5 × 105 ActA- Lm-OVA. Donor OT-I cells were tracked in the spleen and IEL, 2 months p.i.. Graph depicts pooled data ± s.e.m.. (d) As described in (b) and (c), CD8β expression (MFI) was measured on effector WT OT-I or ΔE8I OT-I cells 7 days post oral infection (left) or i.v. infection (right). (e) As described in (c), CD8β expression was measured on memory WT OT-I or ΔE8I OT-I cells 2 m post i.v. infection in the spleen and IEL (f, g) 5 × 104 naïve Ly5.1+Ly5.2+ WT OT-I and 5 × 104 naïve Ly5.2+ ΔE8I OT-I cells were co-transferred into Ly5.1+ WT or Ly5.1+ TL- mice. One day after transfer, the mice were orally infected with 1 × 109 ActA- Lm-OVA. Two months p.i., memory OT-I cells were tracked in the spleen and IEL. (f) Graph depicts pooled data ± s.e.m. (n = 5 per group). (g) Staining for CD8αα expression, using TL-tetramers, on gated memory WT OT-I cells in IEL of WT or TL- recipient mice 2m p.i. * P < 0.001 and ** P < 0.01 (unpaired t-test). Data are representative of three (a, b, c, e, f, g) and two (d) independent experiments.
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Figure 3: Activation-induced CD8αα rescues CD8αβ primary effector T cells from TICD(a) 2 × 105 CFSE-labeled naïve ΔE8I OT-I cells were cultured with 4 × 104 OVAp-pulsed DCs from SPL or mLN of WT or TL- mice that were previously orally infected with ActA- Lm-OVA. After 2 d culture, OT-I cells were harvested and analyzed for cell death by Annexin V staining. (b) 5 × 104 naïve Ly5.2+ WT or Ly5.2+ ΔE8I OT-I cells were adoptively transferred into Ly5.1 recipient mice. 1 d after transfer, mice were orally infected with 1 × 109 ActA- Lm-OVA. Donor OT-I cells were tracked in the spleen and IEL, 2 months p.i.. Graph depicts pooled data ± s.e.m.. (c) 5 × 104 naïve Ly5.2+ WT or Ly5.2+ ΔE8I OT-I cells were adoptively transferred into Ly5.1 recipient mice. 1 d after transfer, mice were intravenously infected with 2.5 × 105 ActA- Lm-OVA. Donor OT-I cells were tracked in the spleen and IEL, 2 months p.i.. Graph depicts pooled data ± s.e.m.. (d) As described in (b) and (c), CD8β expression (MFI) was measured on effector WT OT-I or ΔE8I OT-I cells 7 days post oral infection (left) or i.v. infection (right). (e) As described in (c), CD8β expression was measured on memory WT OT-I or ΔE8I OT-I cells 2 m post i.v. infection in the spleen and IEL (f, g) 5 × 104 naïve Ly5.1+Ly5.2+ WT OT-I and 5 × 104 naïve Ly5.2+ ΔE8I OT-I cells were co-transferred into Ly5.1+ WT or Ly5.1+ TL- mice. One day after transfer, the mice were orally infected with 1 × 109 ActA- Lm-OVA. Two months p.i., memory OT-I cells were tracked in the spleen and IEL. (f) Graph depicts pooled data ± s.e.m. (n = 5 per group). (g) Staining for CD8αα expression, using TL-tetramers, on gated memory WT OT-I cells in IEL of WT or TL- recipient mice 2m p.i. * P < 0.001 and ** P < 0.01 (unpaired t-test). Data are representative of three (a, b, c, e, f, g) and two (d) independent experiments.
Mentions: In contrast to CD8αβ, CD8αα does not function as a TCR co-receptor and similar to TL, CD8αα also does not engage in the TCR activation complex27, 28. However, whereas TL induces death of activated CD8αβ+ T cells, CD8αα, which exhibits a stronger affinity for TL compared to CD8αβ14, promotes the survival of CD8αβ effector cells12, suggesting that activation-induced CD8αα might interfere with TICD. To test this, we compared the survival and memory differentiation of CD8αβ effector T cells in the absence or presence of CD8αα. Due to a deletion of CD8α enhancer region I (Cd8a–E8I)29, OT-I CD8αβ donor cells on the E8I negative background (hereafter called ΔE8I OT-I CD8αβ+T cells do not induce detectable amounts of activation-dependent CD8αα 12. When analyzed in vitro, ΔE8I OT-I CD8αβ+T cells primed by OVA-loaded mLN DCs, which constitutively express TL (Fig. 1e), showed increased activation-induced death compared to their counterparts primed by splenic DCs (Fig. 3a). However, the increase in cell death induced by these mucosal APCs was not observed when mLN and splenic DCs isolated from TL- mice were compared (Fig. 3a).

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