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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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CD8αα expression marks effector memory CD8αβ T cells in humans(a) Expression of CD8αα on polyclonal human naive (TN; CCR7+CD45RA+), recently activated effector-memory (TEMRA; CCR7–CD45RA+), effector-memory (TEM; CCR7–CD45RA–) and central-memory (TCM; CCR7+CD45RA–) CD8+ T cells was measured by TL-tetramer staining. The numbers indicate the percentage of TL-tetramerhi cells. Graph depicts pooled data ± s.e.m. on percentage of CD8αα expression on human peripheral blood CD8+ T cells (n = 9). The differences between TN and TEMRA, TEM or TCM were significant (P < 0.001, unpaired t-test). (b) TL-tetramer staining of human TEMRA CD8+ T cells is blocked by anti-CD8α but not anti-CD8β antibody. Data are representative of two independent experiments. (c) CMVpp65-specific CD8+ T cells display a TEM/TEMRA phenotype and persist at high frequency in humans. Data from two representative donors from a total of six persons are shown. The TL-tetramer staining was absent on naive CD8+ T cells and was blocked by an anti-CD8α.
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Figure 5: CD8αα expression marks effector memory CD8αβ T cells in humans(a) Expression of CD8αα on polyclonal human naive (TN; CCR7+CD45RA+), recently activated effector-memory (TEMRA; CCR7–CD45RA+), effector-memory (TEM; CCR7–CD45RA–) and central-memory (TCM; CCR7+CD45RA–) CD8+ T cells was measured by TL-tetramer staining. The numbers indicate the percentage of TL-tetramerhi cells. Graph depicts pooled data ± s.e.m. on percentage of CD8αα expression on human peripheral blood CD8+ T cells (n = 9). The differences between TN and TEMRA, TEM or TCM were significant (P < 0.001, unpaired t-test). (b) TL-tetramer staining of human TEMRA CD8+ T cells is blocked by anti-CD8α but not anti-CD8β antibody. Data are representative of two independent experiments. (c) CMVpp65-specific CD8+ T cells display a TEM/TEMRA phenotype and persist at high frequency in humans. Data from two representative donors from a total of six persons are shown. The TL-tetramer staining was absent on naive CD8+ T cells and was blocked by an anti-CD8α.

Mentions: Previous evidence indicated that the mouse TL tetramers also detect expression of human CD8αα homodimers12,17. Consistent with activation-induced expression of CD8αα, human CD8αβ effector cells also stained with TL tetramers, whereas naïve T cells did not (Fig. 5a). TL tetramer staining could be blocked with an antibody specific for human CD8α, but not with anti-CD8β, confirming the specificity of the TL tetramer for human CD8αα (Fig. 5b and Supplementary Fig. 4). Furthermore, the subset of immunodominant, high-affinity, CMV-pp65-specific CD8αβ T cells34, isolated from cytomegalovirus (CMV)-sero-positive individuals, stained almost exclusively with TL tetramer, which could be blocked with anti-CD8α (Fig. 5c). These data indicate that CD8αα expression on human CD8αβ effector T cells also is associated with high-affinity effector cells.


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)

CD8αα expression marks effector memory CD8αβ T cells in humans(a) Expression of CD8αα on polyclonal human naive (TN; CCR7+CD45RA+), recently activated effector-memory (TEMRA; CCR7–CD45RA+), effector-memory (TEM; CCR7–CD45RA–) and central-memory (TCM; CCR7+CD45RA–) CD8+ T cells was measured by TL-tetramer staining. The numbers indicate the percentage of TL-tetramerhi cells. Graph depicts pooled data ± s.e.m. on percentage of CD8αα expression on human peripheral blood CD8+ T cells (n = 9). The differences between TN and TEMRA, TEM or TCM were significant (P < 0.001, unpaired t-test). (b) TL-tetramer staining of human TEMRA CD8+ T cells is blocked by anti-CD8α but not anti-CD8β antibody. Data are representative of two independent experiments. (c) CMVpp65-specific CD8+ T cells display a TEM/TEMRA phenotype and persist at high frequency in humans. Data from two representative donors from a total of six persons are shown. The TL-tetramer staining was absent on naive CD8+ T cells and was blocked by an anti-CD8α.
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Related In: Results  -  Collection

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Figure 5: CD8αα expression marks effector memory CD8αβ T cells in humans(a) Expression of CD8αα on polyclonal human naive (TN; CCR7+CD45RA+), recently activated effector-memory (TEMRA; CCR7–CD45RA+), effector-memory (TEM; CCR7–CD45RA–) and central-memory (TCM; CCR7+CD45RA–) CD8+ T cells was measured by TL-tetramer staining. The numbers indicate the percentage of TL-tetramerhi cells. Graph depicts pooled data ± s.e.m. on percentage of CD8αα expression on human peripheral blood CD8+ T cells (n = 9). The differences between TN and TEMRA, TEM or TCM were significant (P < 0.001, unpaired t-test). (b) TL-tetramer staining of human TEMRA CD8+ T cells is blocked by anti-CD8α but not anti-CD8β antibody. Data are representative of two independent experiments. (c) CMVpp65-specific CD8+ T cells display a TEM/TEMRA phenotype and persist at high frequency in humans. Data from two representative donors from a total of six persons are shown. The TL-tetramer staining was absent on naive CD8+ T cells and was blocked by an anti-CD8α.
Mentions: Previous evidence indicated that the mouse TL tetramers also detect expression of human CD8αα homodimers12,17. Consistent with activation-induced expression of CD8αα, human CD8αβ effector cells also stained with TL tetramers, whereas naïve T cells did not (Fig. 5a). TL tetramer staining could be blocked with an antibody specific for human CD8α, but not with anti-CD8β, confirming the specificity of the TL tetramer for human CD8αα (Fig. 5b and Supplementary Fig. 4). Furthermore, the subset of immunodominant, high-affinity, CMV-pp65-specific CD8αβ T cells34, isolated from cytomegalovirus (CMV)-sero-positive individuals, stained almost exclusively with TL tetramer, which could be blocked with anti-CD8α (Fig. 5c). These data indicate that CD8αα expression on human CD8αβ effector T cells also is associated with high-affinity effector cells.

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