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The LCMV gp33-specific memory T cell repertoire narrows with age.

Bunztman A, Vincent BG, Krovi H, Steele S, Frelinger JA - Immun Ageing (2012)

Bottom Line: Thus, a broad polyclonal response is associated with an effective anti-viral CD8+ T cell response.The identical TCRVβ sequences were found in both the tetramerhi and tetramerlo binding populations.This narrowing of the repertoire could contribute to the progressively ineffective immune response seen in aging.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunobiology, University of Arizona, Tucson, AZ, 85724, USA. jfrelin@email.arizona.edu.

ABSTRACT

Background: The memory response to LCMV in mice persists for months to years with only a small decrease in the number of epitope specific CD8 T cells. This long persistence is associated with resistance to lethal LCMV disease. In contrast to studies focused on the number and surface phenotype of the memory cells, relatively little attention has been paid to the diversity of TCR usage in these cells. CD8+ T cell responses with only a few clones of identical specificity are believed to be relatively ineffective, presumably due to the relative ease of virus escape. Thus, a broad polyclonal response is associated with an effective anti-viral CD8+ T cell response.

Results: In this paper we show that the primary CD8+ T cell response to the LCMV gp33-41 epitope is extremely diverse. Over time while the response remains robust in terms of the number of gp33-tetramer+ T cells, the diversity of the response becomes less so. Strikingly, by 26 months after infection the response is dominated by a small number TCRβ sequences. In addition, it is of note the gp33 specific CD8+ T cells sorted by high and low tetramer binding populations 15 and 22 months after infection. High and low tetramer binding cells had equivalent diversity and were dominated by a small number of clones regardless of the time tested. A similar restricted distribution was seen in NP396 specific CD8+ T cells 26 months after infection. The identical TCRVβ sequences were found in both the tetramerhi and tetramerlo binding populations. Finally, we saw no evidence of public clones in the gp33-specific response. No CDR3 sequences were found in more than one mouse.

Conclusions: These data show that following LCMV infection the CD8+ gp33-specific CD8 T cell response becomes highly restricted with enormous narrowing of the diversity. This narrowing of the repertoire could contribute to the progressively ineffective immune response seen in aging.

No MeSH data available.


Related in: MedlinePlus

Shannon Entropy of the TCRVβ usage of gp33 tetramer+ CD8 T cells over time following infection with LCMV. Shannon entropy was calculated for each distribution using the pooled data from tetramer high and low cells at 15 and 22 months. The entropy was calculated separately for the 26 month mice and averaged.
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Figure 2: Shannon Entropy of the TCRVβ usage of gp33 tetramer+ CD8 T cells over time following infection with LCMV. Shannon entropy was calculated for each distribution using the pooled data from tetramer high and low cells at 15 and 22 months. The entropy was calculated separately for the 26 month mice and averaged.

Mentions: Entropy has been used by ecologists to describe the combined species richness (the number of species present) and the distribution of species present (the percentages of the total individuals of each species) [26,27]. This number is analogous to chemical entropy as it measure the total disorder in a system. Thus a population with more species has a higher entropy, as does one with a flatter distribution of the number of individuals of each species. We have chosen to use the Shannon entropy as the index of diversity that accounts for both the number and distribution of species as previously described by our group (41). The entropy is calculated from the sequence data- that is the number and distribution of VJ and CDR3. When we compared the entropy between the day 23 and naïve T cells, both had similar, large entropy (6.4 compared to 6.5) (Figure 2), consistent with high species richness and the lack of dominant clones. Based on the spectratyping analysis of B6 mice we had expected the number of T cell receptor CDR3 to be relatively restricted [13]. Instead we found TRVβ13 genes were used as predicted although they represented only a small fraction (8%) of the gp33 response. This indicates that spectratyping can significantly underestimate the diversity of the T cell receptors used. We emphasize that these sequences came from tetramer sorted single cells.


The LCMV gp33-specific memory T cell repertoire narrows with age.

Bunztman A, Vincent BG, Krovi H, Steele S, Frelinger JA - Immun Ageing (2012)

Shannon Entropy of the TCRVβ usage of gp33 tetramer+ CD8 T cells over time following infection with LCMV. Shannon entropy was calculated for each distribution using the pooled data from tetramer high and low cells at 15 and 22 months. The entropy was calculated separately for the 26 month mice and averaged.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472190&req=5

Figure 2: Shannon Entropy of the TCRVβ usage of gp33 tetramer+ CD8 T cells over time following infection with LCMV. Shannon entropy was calculated for each distribution using the pooled data from tetramer high and low cells at 15 and 22 months. The entropy was calculated separately for the 26 month mice and averaged.
Mentions: Entropy has been used by ecologists to describe the combined species richness (the number of species present) and the distribution of species present (the percentages of the total individuals of each species) [26,27]. This number is analogous to chemical entropy as it measure the total disorder in a system. Thus a population with more species has a higher entropy, as does one with a flatter distribution of the number of individuals of each species. We have chosen to use the Shannon entropy as the index of diversity that accounts for both the number and distribution of species as previously described by our group (41). The entropy is calculated from the sequence data- that is the number and distribution of VJ and CDR3. When we compared the entropy between the day 23 and naïve T cells, both had similar, large entropy (6.4 compared to 6.5) (Figure 2), consistent with high species richness and the lack of dominant clones. Based on the spectratyping analysis of B6 mice we had expected the number of T cell receptor CDR3 to be relatively restricted [13]. Instead we found TRVβ13 genes were used as predicted although they represented only a small fraction (8%) of the gp33 response. This indicates that spectratyping can significantly underestimate the diversity of the T cell receptors used. We emphasize that these sequences came from tetramer sorted single cells.

Bottom Line: Thus, a broad polyclonal response is associated with an effective anti-viral CD8+ T cell response.The identical TCRVβ sequences were found in both the tetramerhi and tetramerlo binding populations.This narrowing of the repertoire could contribute to the progressively ineffective immune response seen in aging.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunobiology, University of Arizona, Tucson, AZ, 85724, USA. jfrelin@email.arizona.edu.

ABSTRACT

Background: The memory response to LCMV in mice persists for months to years with only a small decrease in the number of epitope specific CD8 T cells. This long persistence is associated with resistance to lethal LCMV disease. In contrast to studies focused on the number and surface phenotype of the memory cells, relatively little attention has been paid to the diversity of TCR usage in these cells. CD8+ T cell responses with only a few clones of identical specificity are believed to be relatively ineffective, presumably due to the relative ease of virus escape. Thus, a broad polyclonal response is associated with an effective anti-viral CD8+ T cell response.

Results: In this paper we show that the primary CD8+ T cell response to the LCMV gp33-41 epitope is extremely diverse. Over time while the response remains robust in terms of the number of gp33-tetramer+ T cells, the diversity of the response becomes less so. Strikingly, by 26 months after infection the response is dominated by a small number TCRβ sequences. In addition, it is of note the gp33 specific CD8+ T cells sorted by high and low tetramer binding populations 15 and 22 months after infection. High and low tetramer binding cells had equivalent diversity and were dominated by a small number of clones regardless of the time tested. A similar restricted distribution was seen in NP396 specific CD8+ T cells 26 months after infection. The identical TCRVβ sequences were found in both the tetramerhi and tetramerlo binding populations. Finally, we saw no evidence of public clones in the gp33-specific response. No CDR3 sequences were found in more than one mouse.

Conclusions: These data show that following LCMV infection the CD8+ gp33-specific CD8 T cell response becomes highly restricted with enormous narrowing of the diversity. This narrowing of the repertoire could contribute to the progressively ineffective immune response seen in aging.

No MeSH data available.


Related in: MedlinePlus