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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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TL mediates death of activated CD8αβ+ T cells(a) 1 × 106 naïve Ly5.1+ OT-I cells were transferred into WT or TL-Tg recipients and the donor cells in the spleens were tracked one month after transfer (top, n = 5 per group). 1 × 106in vitro activated Ly5.1+ OT-I cells were transferred into WT or TL-Tg recipients and the donor cells in the spleen were tracked one month after transfer (bottom, n = 8 per group). (b) Naïve CD8 T cells sorted from WT, FasLgld or Faslpr mice were stimulated in vitro by anti-CD3/-CD28 beads for 3 d. 0.5 × 106 activated CD8 T cells were transferred into Ly5.1+ WT or TL-Tg recipients and the donor cells in the spleens were tracked 1 month after transfer. Representative data are shown of four mice analyzed in each group. Data are representative of two independent experiments (a, b).
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Figure 2: TL mediates death of activated CD8αβ+ T cells(a) 1 × 106 naïve Ly5.1+ OT-I cells were transferred into WT or TL-Tg recipients and the donor cells in the spleens were tracked one month after transfer (top, n = 5 per group). 1 × 106in vitro activated Ly5.1+ OT-I cells were transferred into WT or TL-Tg recipients and the donor cells in the spleen were tracked one month after transfer (bottom, n = 8 per group). (b) Naïve CD8 T cells sorted from WT, FasLgld or Faslpr mice were stimulated in vitro by anti-CD3/-CD28 beads for 3 d. 0.5 × 106 activated CD8 T cells were transferred into Ly5.1+ WT or TL-Tg recipients and the donor cells in the spleens were tracked 1 month after transfer. Representative data are shown of four mice analyzed in each group. Data are representative of two independent experiments (a, b).

Mentions: Although TL displays structural characteristics of MHC class I molecules, it does not function as a typical antigen-presenting molecule. The narrow distance between the α helices that form the boundaries of the antigen binding groove will not permit TL peptide binding and presentation22 and therefore TL fails to engage with the αβ TCR. Nevertheless the high degree of conserved sequence in the α3 domain allows TL to interact with the CD8αβ co-receptor, despite the exclusion of TL from the TCR activation complex14. A similar interaction of soluble HLA class I molecules with CD8αβ TCR co-receptor, separately from TCR ligation, was previously shown to lead to Fas-FasL-induced cell death23-26. To investigate if the TL interaction with CD8αβ on activated T cells might also lead to cell death, we measured the survival of naïve and antigen stimulated CD8αβ cells in the presence of constitutive TL expression in TL-Tg hosts. Whereas naïve donor cells survived similarly in wild-type or TL-Tg mice, activated CD8αβ+ OT-I cells survived only in wild-type but not in TL-Tg hosts (Fig. 2a), supporting the notion that TL-induced cell death (TICD) targets activated CD8αβ+ T cells. Activated Fas-deficient (Faslpr/lpr) CD8αβ+ donor T cells, however, were not deleted in TL-Tg recipient mice, providing evidence that, similar to the reported death by soluble HLA-G23, 24, TICD also involves the Fas–FasL-mediated death pathway (Fig. 2b).


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)

TL mediates death of activated CD8αβ+ T cells(a) 1 × 106 naïve Ly5.1+ OT-I cells were transferred into WT or TL-Tg recipients and the donor cells in the spleens were tracked one month after transfer (top, n = 5 per group). 1 × 106in vitro activated Ly5.1+ OT-I cells were transferred into WT or TL-Tg recipients and the donor cells in the spleen were tracked one month after transfer (bottom, n = 8 per group). (b) Naïve CD8 T cells sorted from WT, FasLgld or Faslpr mice were stimulated in vitro by anti-CD3/-CD28 beads for 3 d. 0.5 × 106 activated CD8 T cells were transferred into Ly5.1+ WT or TL-Tg recipients and the donor cells in the spleens were tracked 1 month after transfer. Representative data are shown of four mice analyzed in each group. Data are representative of two independent experiments (a, b).
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Figure 2: TL mediates death of activated CD8αβ+ T cells(a) 1 × 106 naïve Ly5.1+ OT-I cells were transferred into WT or TL-Tg recipients and the donor cells in the spleens were tracked one month after transfer (top, n = 5 per group). 1 × 106in vitro activated Ly5.1+ OT-I cells were transferred into WT or TL-Tg recipients and the donor cells in the spleen were tracked one month after transfer (bottom, n = 8 per group). (b) Naïve CD8 T cells sorted from WT, FasLgld or Faslpr mice were stimulated in vitro by anti-CD3/-CD28 beads for 3 d. 0.5 × 106 activated CD8 T cells were transferred into Ly5.1+ WT or TL-Tg recipients and the donor cells in the spleens were tracked 1 month after transfer. Representative data are shown of four mice analyzed in each group. Data are representative of two independent experiments (a, b).
Mentions: Although TL displays structural characteristics of MHC class I molecules, it does not function as a typical antigen-presenting molecule. The narrow distance between the α helices that form the boundaries of the antigen binding groove will not permit TL peptide binding and presentation22 and therefore TL fails to engage with the αβ TCR. Nevertheless the high degree of conserved sequence in the α3 domain allows TL to interact with the CD8αβ co-receptor, despite the exclusion of TL from the TCR activation complex14. A similar interaction of soluble HLA class I molecules with CD8αβ TCR co-receptor, separately from TCR ligation, was previously shown to lead to Fas-FasL-induced cell death23-26. To investigate if the TL interaction with CD8αβ on activated T cells might also lead to cell death, we measured the survival of naïve and antigen stimulated CD8αβ cells in the presence of constitutive TL expression in TL-Tg hosts. Whereas naïve donor cells survived similarly in wild-type or TL-Tg mice, activated CD8αβ+ OT-I cells survived only in wild-type but not in TL-Tg hosts (Fig. 2a), supporting the notion that TL-induced cell death (TICD) targets activated CD8αβ+ T cells. Activated Fas-deficient (Faslpr/lpr) CD8αβ+ donor T cells, however, were not deleted in TL-Tg recipient mice, providing evidence that, similar to the reported death by soluble HLA-G23, 24, TICD also involves the Fas–FasL-mediated death pathway (Fig. 2b).

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