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Characterization of CD8+ T cell differentiation following SIVΔnef vaccination by transcription factor expression profiling.

Billingsley JM, Rajakumar PA, Connole MA, Salisch NC, Adnan S, Kuzmichev YV, Hong HS, Reeves RK, Kang HJ, Li W, Li Q, Haase AT, Johnson RP - PLoS Pathog. (2015)

Bottom Line: The onset of protective immunity against pathogenic SIV challenge in SIVΔnef-vaccinated macaques is delayed for 15-20 weeks, a process that is related to qualitative changes in CD8+ T cell responses induced by SIVΔnef.Expression of transcription factors associated with effector differentiation, such as ID2 and RUNX3, were decreased over time, while expression of transcription factors associated with quiescence or memory differentiation, such as TCF7, BCOR and EOMES, increased.These data suggest transcription factor expression profiling is a novel method that can provide additional data complementary to the analysis of memory cell differentiation based on classical phenotypic markers.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, United States of America; Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.

ABSTRACT
The onset of protective immunity against pathogenic SIV challenge in SIVΔnef-vaccinated macaques is delayed for 15-20 weeks, a process that is related to qualitative changes in CD8+ T cell responses induced by SIVΔnef. As a novel approach to characterize cell differentiation following vaccination, we used multi-target qPCR to measure transcription factor expression in naïve and memory subsets of CD8++ T cells, and in SIV-specific CD8+ T cells obtained from SIVΔnef-vaccinated or wild type SIVmac239-infected macaques. Unsupervised clustering of expression profiles organized naïve and memory CD8+ T cells into groups concordant with cell surface phenotype. Transcription factor expression patterns in SIV-specific CD8+ T cells in SIVΔnef-vaccinated animals were distinct from those observed in purified CD8+ T cell subsets obtained from naïve animals, and were intermediate to expression profiles of purified central memory and effector memory T cells. Expression of transcription factors elicited by SIVΔnef vaccination also varied over time: cells obtained at later time points, temporally associated with greater protection, appeared more central-memory like than cells obtained at earlier time points, which appeared more effector memory-like. Expression of transcription factors associated with effector differentiation, such as ID2 and RUNX3, were decreased over time, while expression of transcription factors associated with quiescence or memory differentiation, such as TCF7, BCOR and EOMES, increased. CD8+ T cells specific for a more conserved epitope expressed higher levels of TBX21 and BATF, and appeared more effector-like than cells specific for an escaped epitope, consistent with continued activation by replicating vaccine virus. These data suggest transcription factor expression profiling is a novel method that can provide additional data complementary to the analysis of memory cell differentiation based on classical phenotypic markers. Additionally, these data support the hypothesis that ongoing stimulation by SIVΔnef promotes a distinct protective balance of CD8+ T cell differentiation and activation states.

No MeSH data available.


Related in: MedlinePlus

Differential expression of transcription factors in CD8+ T cells isolated at week 5 and week 20 post-vaccination with SIVΔnef and at week 20 post-infection with wild-type SIV.Symbols indicate log2 expression relative to endogenous controls in cells from individual animals. Red symbols indicate Gag CM9-specific cells, blue symbols indicate Tat SL8-specific cells. Sample means are indicated by horizontal bars. Statistically significant (p≤0.05) differences in transcription factor expression between cells from week 5 and week 20 post-SIVΔnef vaccination, or between cells from week 20 post-SIVΔnef vaccination and week 20 post-wild-type SIV infection are indicated by horizontal bars with asterisks. Statistically significant differences between Gag CM9 and Tat SL8-specific cells are indicated by vertical bars with asterisks.
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ppat.1004740.g005: Differential expression of transcription factors in CD8+ T cells isolated at week 5 and week 20 post-vaccination with SIVΔnef and at week 20 post-infection with wild-type SIV.Symbols indicate log2 expression relative to endogenous controls in cells from individual animals. Red symbols indicate Gag CM9-specific cells, blue symbols indicate Tat SL8-specific cells. Sample means are indicated by horizontal bars. Statistically significant (p≤0.05) differences in transcription factor expression between cells from week 5 and week 20 post-SIVΔnef vaccination, or between cells from week 20 post-SIVΔnef vaccination and week 20 post-wild-type SIV infection are indicated by horizontal bars with asterisks. Statistically significant differences between Gag CM9 and Tat SL8-specific cells are indicated by vertical bars with asterisks.

Mentions: A number of individual transcription factors were significantly differentially expressed between week 5 post-vaccination and week 20 post-vaccination (Fig. 5). For example BCOR, EOMES and TCF7 were expressed at significantly higher levels at week 20 post-vaccination. Higher expression of these transcription factors is consistent with a more quiescent and central memory-like phenotype [44,45,54]. Conversely, ID2, RORA, NFIL3 and RUNX3 were expressed at significantly lower levels at week 20 post-vaccination. Lower expression of ID2 and RUNX3 is also consistent with a more central memory-like phenotype [35,40]. Elevated TBX21 expression, which is associated with effector differentiation, however, was maintained at week 20, consistent with continued effector function [28,29].


Characterization of CD8+ T cell differentiation following SIVΔnef vaccination by transcription factor expression profiling.

Billingsley JM, Rajakumar PA, Connole MA, Salisch NC, Adnan S, Kuzmichev YV, Hong HS, Reeves RK, Kang HJ, Li W, Li Q, Haase AT, Johnson RP - PLoS Pathog. (2015)

Differential expression of transcription factors in CD8+ T cells isolated at week 5 and week 20 post-vaccination with SIVΔnef and at week 20 post-infection with wild-type SIV.Symbols indicate log2 expression relative to endogenous controls in cells from individual animals. Red symbols indicate Gag CM9-specific cells, blue symbols indicate Tat SL8-specific cells. Sample means are indicated by horizontal bars. Statistically significant (p≤0.05) differences in transcription factor expression between cells from week 5 and week 20 post-SIVΔnef vaccination, or between cells from week 20 post-SIVΔnef vaccination and week 20 post-wild-type SIV infection are indicated by horizontal bars with asterisks. Statistically significant differences between Gag CM9 and Tat SL8-specific cells are indicated by vertical bars with asterisks.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358830&req=5

ppat.1004740.g005: Differential expression of transcription factors in CD8+ T cells isolated at week 5 and week 20 post-vaccination with SIVΔnef and at week 20 post-infection with wild-type SIV.Symbols indicate log2 expression relative to endogenous controls in cells from individual animals. Red symbols indicate Gag CM9-specific cells, blue symbols indicate Tat SL8-specific cells. Sample means are indicated by horizontal bars. Statistically significant (p≤0.05) differences in transcription factor expression between cells from week 5 and week 20 post-SIVΔnef vaccination, or between cells from week 20 post-SIVΔnef vaccination and week 20 post-wild-type SIV infection are indicated by horizontal bars with asterisks. Statistically significant differences between Gag CM9 and Tat SL8-specific cells are indicated by vertical bars with asterisks.
Mentions: A number of individual transcription factors were significantly differentially expressed between week 5 post-vaccination and week 20 post-vaccination (Fig. 5). For example BCOR, EOMES and TCF7 were expressed at significantly higher levels at week 20 post-vaccination. Higher expression of these transcription factors is consistent with a more quiescent and central memory-like phenotype [44,45,54]. Conversely, ID2, RORA, NFIL3 and RUNX3 were expressed at significantly lower levels at week 20 post-vaccination. Lower expression of ID2 and RUNX3 is also consistent with a more central memory-like phenotype [35,40]. Elevated TBX21 expression, which is associated with effector differentiation, however, was maintained at week 20, consistent with continued effector function [28,29].

Bottom Line: The onset of protective immunity against pathogenic SIV challenge in SIVΔnef-vaccinated macaques is delayed for 15-20 weeks, a process that is related to qualitative changes in CD8+ T cell responses induced by SIVΔnef.Expression of transcription factors associated with effector differentiation, such as ID2 and RUNX3, were decreased over time, while expression of transcription factors associated with quiescence or memory differentiation, such as TCF7, BCOR and EOMES, increased.These data suggest transcription factor expression profiling is a novel method that can provide additional data complementary to the analysis of memory cell differentiation based on classical phenotypic markers.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, United States of America; Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.

ABSTRACT
The onset of protective immunity against pathogenic SIV challenge in SIVΔnef-vaccinated macaques is delayed for 15-20 weeks, a process that is related to qualitative changes in CD8+ T cell responses induced by SIVΔnef. As a novel approach to characterize cell differentiation following vaccination, we used multi-target qPCR to measure transcription factor expression in naïve and memory subsets of CD8++ T cells, and in SIV-specific CD8+ T cells obtained from SIVΔnef-vaccinated or wild type SIVmac239-infected macaques. Unsupervised clustering of expression profiles organized naïve and memory CD8+ T cells into groups concordant with cell surface phenotype. Transcription factor expression patterns in SIV-specific CD8+ T cells in SIVΔnef-vaccinated animals were distinct from those observed in purified CD8+ T cell subsets obtained from naïve animals, and were intermediate to expression profiles of purified central memory and effector memory T cells. Expression of transcription factors elicited by SIVΔnef vaccination also varied over time: cells obtained at later time points, temporally associated with greater protection, appeared more central-memory like than cells obtained at earlier time points, which appeared more effector memory-like. Expression of transcription factors associated with effector differentiation, such as ID2 and RUNX3, were decreased over time, while expression of transcription factors associated with quiescence or memory differentiation, such as TCF7, BCOR and EOMES, increased. CD8+ T cells specific for a more conserved epitope expressed higher levels of TBX21 and BATF, and appeared more effector-like than cells specific for an escaped epitope, consistent with continued activation by replicating vaccine virus. These data suggest transcription factor expression profiling is a novel method that can provide additional data complementary to the analysis of memory cell differentiation based on classical phenotypic markers. Additionally, these data support the hypothesis that ongoing stimulation by SIVΔnef promotes a distinct protective balance of CD8+ T cell differentiation and activation states.

No MeSH data available.


Related in: MedlinePlus