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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

Pinwheel depiction of TCR usage of NP396 specific CD8+ T cells sorted from 26 month post LCMV infection mice. The NP396 cells are sorted from the same mice in the previous experiments. Mouse 1 is represented by 27 sequences and mouse 2 by 66 sequences.
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Figure 8: Pinwheel depiction of TCR usage of NP396 specific CD8+ T cells sorted from 26 month post LCMV infection mice. The NP396 cells are sorted from the same mice in the previous experiments. Mouse 1 is represented by 27 sequences and mouse 2 by 66 sequences.

Mentions: To determine if this phenomenon was limited to gp33 specific T cells we sequenced NP396 specific T CD8+ T cells at 26 months in the same mice that were donors for the gp33-specific T cells. Figure 8 shows the usage of TRVβ, Jβ and Vβ/ Jβ pairs in these mice. As we saw with the gp33 specific T cells, the NP396 specific T cells also had a restricted repertoire compared to the naïve cells (Figure 1 compared to Figure 8). These NP396 tetramer+ T cells represented 2.5% and 0.6% of the CD8+ T cells from 2 mice, so their frequency was similar to that of the gp33 specific T cells. The calculated entropies of 3.4 and 2.5, is very similar to those found in the gp33 tetramer+ CD8+ T cells. Thus, although we do not have data from earlier time points for the NP396 specific T cells, in old mice the memory repertoire was similarly contracted to the gp33 specific repertoire.


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

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

Pinwheel depiction of TCR usage of NP396 specific CD8+ T cells sorted from 26 month post LCMV infection mice. The NP396 cells are sorted from the same mice in the previous experiments. Mouse 1 is represented by 27 sequences and mouse 2 by 66 sequences.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Pinwheel depiction of TCR usage of NP396 specific CD8+ T cells sorted from 26 month post LCMV infection mice. The NP396 cells are sorted from the same mice in the previous experiments. Mouse 1 is represented by 27 sequences and mouse 2 by 66 sequences.
Mentions: To determine if this phenomenon was limited to gp33 specific T cells we sequenced NP396 specific T CD8+ T cells at 26 months in the same mice that were donors for the gp33-specific T cells. Figure 8 shows the usage of TRVβ, Jβ and Vβ/ Jβ pairs in these mice. As we saw with the gp33 specific T cells, the NP396 specific T cells also had a restricted repertoire compared to the naïve cells (Figure 1 compared to Figure 8). These NP396 tetramer+ T cells represented 2.5% and 0.6% of the CD8+ T cells from 2 mice, so their frequency was similar to that of the gp33 specific T cells. The calculated entropies of 3.4 and 2.5, is very similar to those found in the gp33 tetramer+ CD8+ T cells. Thus, although we do not have data from earlier time points for the NP396 specific T cells, in old mice the memory repertoire was similarly contracted to the gp33 specific repertoire.

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