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Selective expansion of cross-reactive CD8(+) memory T cells by viral variants.

Haanen JB, Wolkers MC, Kruisbeek AM, Schumacher TN - J. Exp. Med. (1999)

Bottom Line: The role of memory T cells during the immune response against random antigenic variants has not been resolved.Here, we show by simultaneous staining with two tetrameric major histocompatibility complex (MHC)-peptide molecules, that the polyclonal CD8(+) T cell response against a series of natural variants of the influenza A nucleoprotein epitope is completely dominated by infrequent cross-reactive T cells that expand from an original memory population.These results provide direct evidence that the repertoire of antigen-specific T cells used during an infection critically depends on prior antigen encounters, and indicate that polyclonal memory T cell populations can provide protection against a range of antigenic variants.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.

ABSTRACT
The role of memory T cells during the immune response against random antigenic variants has not been resolved. Here, we show by simultaneous staining with two tetrameric major histocompatibility complex (MHC)-peptide molecules, that the polyclonal CD8(+) T cell response against a series of natural variants of the influenza A nucleoprotein epitope is completely dominated by infrequent cross-reactive T cells that expand from an original memory population. Based on both biochemical and functional criteria, these cross-reactive cytotoxic T cells productively recognize both the parental and the mutant epitope in vitro and in vivo. These results provide direct evidence that the repertoire of antigen-specific T cells used during an infection critically depends on prior antigen encounters, and indicate that polyclonal memory T cell populations can provide protection against a range of antigenic variants.

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Cross-reactive cells are oligoclonal T memory cell expansions. (A) Cross-reactive CD8+ T cells display a restricted BV repertoire. Naive (top) or A/NT/60/68-primed mice (bottom) were infected with 10 and 200 HAU of influenza A/PR/8/34, respectively. At 7 d after infection, lung-infiltrating A/PR/8/34-specific CD8+ T cells were analyzed for expression of a series of BV elements by using a panel of fluorochrome-labeled anti-BV antibodies (PharMingen). Values represent the percentage of A/PR/8/34-specific CD8+ T cells that stain with a particular anti-BV antibody. (B) Mice were sequentially infected with influenza virus A/HKx31 and A/NT/60/68. 7 d after the second infection, mononuclear cells recovered from pulmonary tissue were stained with anti-CD8 and APC-labeled MHC tetramers with the influenza A/NT/60/68 epitope and PE-labeled MHC tetramers with the influenza A/PR/8/34 epitope, and analyzed by FACS® analysis. The dot plot reveals three distinct populations of selectively expanded cross-reactive CD8+ T cells.
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Figure 3: Cross-reactive cells are oligoclonal T memory cell expansions. (A) Cross-reactive CD8+ T cells display a restricted BV repertoire. Naive (top) or A/NT/60/68-primed mice (bottom) were infected with 10 and 200 HAU of influenza A/PR/8/34, respectively. At 7 d after infection, lung-infiltrating A/PR/8/34-specific CD8+ T cells were analyzed for expression of a series of BV elements by using a panel of fluorochrome-labeled anti-BV antibodies (PharMingen). Values represent the percentage of A/PR/8/34-specific CD8+ T cells that stain with a particular anti-BV antibody. (B) Mice were sequentially infected with influenza virus A/HKx31 and A/NT/60/68. 7 d after the second infection, mononuclear cells recovered from pulmonary tissue were stained with anti-CD8 and APC-labeled MHC tetramers with the influenza A/NT/60/68 epitope and PE-labeled MHC tetramers with the influenza A/PR/8/34 epitope, and analyzed by FACS® analysis. The dot plot reveals three distinct populations of selectively expanded cross-reactive CD8+ T cells.

Mentions: To better understand the ontogeny of the cross-reactive T cell population, we examined the kinetics and composition of this T cell pool. The cross-reactive cytotoxic T cell population appears 2–3 d earlier at the site of infection (i.e., pulmonary tissue; data not shown) than the antigen-specific T cells during infection of naive mice 151617, suggesting that these cells originate from a preexisting memory T cell population. Several studies have shown a narrowing of the antigen-specific polyclonal TCR repertoire during recall infection, due to the preferential outgrowth of a subpopulation of memory cells 30313233. In naive mice that are infected with influenza virus A/PR/8/34, the repertoire of NP-specific T cells involves a variety of BV elements (Fig. 3 A). The slight preferential usage of the BV8.3 element reported previously for C57BL animals infected with influenza virus A/PR8/34 was not observed in these experiments 34. In contrast, in A/NT/60/68-primed mice that are infected with influenza virus A/PR/8/34, the repertoire of A/PR/8/34-specific T cells is highly restricted (Fig. 3 A). This narrow T cell repertoire is likely to reflect the affinity maturation observed previously 33 compounded by the low number of cross-reactive T cells within the original memory population. In certain animals, the oligoclonal nature of the cross-reactive T cell population appears to be directly visible from double-tetramer analyses of the influenza-reactive CD8+ T cell population. In these mice, the expanded cross-reactive T cell population appears as two to three separate populations (an example is shown as Fig. 3 B), which may reflect slightly distinct affinities for the primary and secondary antigen.


Selective expansion of cross-reactive CD8(+) memory T cells by viral variants.

Haanen JB, Wolkers MC, Kruisbeek AM, Schumacher TN - J. Exp. Med. (1999)

Cross-reactive cells are oligoclonal T memory cell expansions. (A) Cross-reactive CD8+ T cells display a restricted BV repertoire. Naive (top) or A/NT/60/68-primed mice (bottom) were infected with 10 and 200 HAU of influenza A/PR/8/34, respectively. At 7 d after infection, lung-infiltrating A/PR/8/34-specific CD8+ T cells were analyzed for expression of a series of BV elements by using a panel of fluorochrome-labeled anti-BV antibodies (PharMingen). Values represent the percentage of A/PR/8/34-specific CD8+ T cells that stain with a particular anti-BV antibody. (B) Mice were sequentially infected with influenza virus A/HKx31 and A/NT/60/68. 7 d after the second infection, mononuclear cells recovered from pulmonary tissue were stained with anti-CD8 and APC-labeled MHC tetramers with the influenza A/NT/60/68 epitope and PE-labeled MHC tetramers with the influenza A/PR/8/34 epitope, and analyzed by FACS® analysis. The dot plot reveals three distinct populations of selectively expanded cross-reactive CD8+ T cells.
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Related In: Results  -  Collection

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Figure 3: Cross-reactive cells are oligoclonal T memory cell expansions. (A) Cross-reactive CD8+ T cells display a restricted BV repertoire. Naive (top) or A/NT/60/68-primed mice (bottom) were infected with 10 and 200 HAU of influenza A/PR/8/34, respectively. At 7 d after infection, lung-infiltrating A/PR/8/34-specific CD8+ T cells were analyzed for expression of a series of BV elements by using a panel of fluorochrome-labeled anti-BV antibodies (PharMingen). Values represent the percentage of A/PR/8/34-specific CD8+ T cells that stain with a particular anti-BV antibody. (B) Mice were sequentially infected with influenza virus A/HKx31 and A/NT/60/68. 7 d after the second infection, mononuclear cells recovered from pulmonary tissue were stained with anti-CD8 and APC-labeled MHC tetramers with the influenza A/NT/60/68 epitope and PE-labeled MHC tetramers with the influenza A/PR/8/34 epitope, and analyzed by FACS® analysis. The dot plot reveals three distinct populations of selectively expanded cross-reactive CD8+ T cells.
Mentions: To better understand the ontogeny of the cross-reactive T cell population, we examined the kinetics and composition of this T cell pool. The cross-reactive cytotoxic T cell population appears 2–3 d earlier at the site of infection (i.e., pulmonary tissue; data not shown) than the antigen-specific T cells during infection of naive mice 151617, suggesting that these cells originate from a preexisting memory T cell population. Several studies have shown a narrowing of the antigen-specific polyclonal TCR repertoire during recall infection, due to the preferential outgrowth of a subpopulation of memory cells 30313233. In naive mice that are infected with influenza virus A/PR/8/34, the repertoire of NP-specific T cells involves a variety of BV elements (Fig. 3 A). The slight preferential usage of the BV8.3 element reported previously for C57BL animals infected with influenza virus A/PR8/34 was not observed in these experiments 34. In contrast, in A/NT/60/68-primed mice that are infected with influenza virus A/PR/8/34, the repertoire of A/PR/8/34-specific T cells is highly restricted (Fig. 3 A). This narrow T cell repertoire is likely to reflect the affinity maturation observed previously 33 compounded by the low number of cross-reactive T cells within the original memory population. In certain animals, the oligoclonal nature of the cross-reactive T cell population appears to be directly visible from double-tetramer analyses of the influenza-reactive CD8+ T cell population. In these mice, the expanded cross-reactive T cell population appears as two to three separate populations (an example is shown as Fig. 3 B), which may reflect slightly distinct affinities for the primary and secondary antigen.

Bottom Line: The role of memory T cells during the immune response against random antigenic variants has not been resolved.Here, we show by simultaneous staining with two tetrameric major histocompatibility complex (MHC)-peptide molecules, that the polyclonal CD8(+) T cell response against a series of natural variants of the influenza A nucleoprotein epitope is completely dominated by infrequent cross-reactive T cells that expand from an original memory population.These results provide direct evidence that the repertoire of antigen-specific T cells used during an infection critically depends on prior antigen encounters, and indicate that polyclonal memory T cell populations can provide protection against a range of antigenic variants.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.

ABSTRACT
The role of memory T cells during the immune response against random antigenic variants has not been resolved. Here, we show by simultaneous staining with two tetrameric major histocompatibility complex (MHC)-peptide molecules, that the polyclonal CD8(+) T cell response against a series of natural variants of the influenza A nucleoprotein epitope is completely dominated by infrequent cross-reactive T cells that expand from an original memory population. Based on both biochemical and functional criteria, these cross-reactive cytotoxic T cells productively recognize both the parental and the mutant epitope in vitro and in vivo. These results provide direct evidence that the repertoire of antigen-specific T cells used during an infection critically depends on prior antigen encounters, and indicate that polyclonal memory T cell populations can provide protection against a range of antigenic variants.

Show MeSH
Related in: MedlinePlus