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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 the TCRVβ usage of gp33-tetramer+ cells following infection with LCMV. Naive represents the unimmunized repertoire. Each pinwheel represents the distribution of TCRVβ from tetramer sorted cells from a single mouse. Two mice were tested at 26 months, designated #1 and #2. The number of cells sequenced in each pinwheel is: naïve, 55; 23 Days, 136; 15 months, 705; 22 months, 187; months 26 mouse 1, 60; 26 months mouse 2, 64. The entire CDR3 sequences have been deposited in Genbank, Accession numbers: [Genbank:JX277204 – JX277543].
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Figure 1: Pinwheel depiction of the TCRVβ usage of gp33-tetramer+ cells following infection with LCMV. Naive represents the unimmunized repertoire. Each pinwheel represents the distribution of TCRVβ from tetramer sorted cells from a single mouse. Two mice were tested at 26 months, designated #1 and #2. The number of cells sequenced in each pinwheel is: naïve, 55; 23 Days, 136; 15 months, 705; 22 months, 187; months 26 mouse 1, 60; 26 months mouse 2, 64. The entire CDR3 sequences have been deposited in Genbank, Accession numbers: [Genbank:JX277204 – JX277543].

Mentions: We report here 55 randomly sequenced TCRβ sequences. In addition we have sequenced 120,000 TCR Vβ from unselected B6 splenic T cells (Buntzman, Krovi and Frelinger, unpublished). These sequences have a similar distribution of Vβ usage consistent with previous work by others (reviewed in [25]). The Vβ usage in the 55 single cells is reported here and is shown in Figure 1. When we sequenced TCRβ from gp33 sorted CD8+ T cells 23 days following infection with LCMV, we found 132 different sequences (Additional file 1: Table S1). Eight per cent were TRVβ13-3 (Figure 1). However we also found 10% TRVβ12-2 and nearly equivalent numbers of TRVβ3, TRVβ12-1 TRVβ16 and TRVβ30. We compared the pattern of Vβ usage between the naïve and 23 day post infection V gene usage and found a significant correlation (p < .003) demonstrating that the initial gp33 specific repertoire is large and representative of the overall diversity.


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 the TCRVβ usage of gp33-tetramer+ cells following infection with LCMV. Naive represents the unimmunized repertoire. Each pinwheel represents the distribution of TCRVβ from tetramer sorted cells from a single mouse. Two mice were tested at 26 months, designated #1 and #2. The number of cells sequenced in each pinwheel is: naïve, 55; 23 Days, 136; 15 months, 705; 22 months, 187; months 26 mouse 1, 60; 26 months mouse 2, 64. The entire CDR3 sequences have been deposited in Genbank, Accession numbers: [Genbank:JX277204 – JX277543].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Pinwheel depiction of the TCRVβ usage of gp33-tetramer+ cells following infection with LCMV. Naive represents the unimmunized repertoire. Each pinwheel represents the distribution of TCRVβ from tetramer sorted cells from a single mouse. Two mice were tested at 26 months, designated #1 and #2. The number of cells sequenced in each pinwheel is: naïve, 55; 23 Days, 136; 15 months, 705; 22 months, 187; months 26 mouse 1, 60; 26 months mouse 2, 64. The entire CDR3 sequences have been deposited in Genbank, Accession numbers: [Genbank:JX277204 – JX277543].
Mentions: We report here 55 randomly sequenced TCRβ sequences. In addition we have sequenced 120,000 TCR Vβ from unselected B6 splenic T cells (Buntzman, Krovi and Frelinger, unpublished). These sequences have a similar distribution of Vβ usage consistent with previous work by others (reviewed in [25]). The Vβ usage in the 55 single cells is reported here and is shown in Figure 1. When we sequenced TCRβ from gp33 sorted CD8+ T cells 23 days following infection with LCMV, we found 132 different sequences (Additional file 1: Table S1). Eight per cent were TRVβ13-3 (Figure 1). However we also found 10% TRVβ12-2 and nearly equivalent numbers of TRVβ3, TRVβ12-1 TRVβ16 and TRVβ30. We compared the pattern of Vβ usage between the naïve and 23 day post infection V gene usage and found a significant correlation (p < .003) demonstrating that the initial gp33 specific repertoire is large and representative of the overall diversity.

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