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CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire.

Publication ,  Journal Article
Suessmuth, Y; Mukherjee, R; Watkins, B; Koura, DT; Finstermeier, K; Desmarais, C; Stempora, L; Horan, JT; Langston, A; Qayed, M; Khoury, HJ ...
Published in: Blood
June 18, 2015

Although cytomegalovirus (CMV) reactivation has long been implicated in posttransplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T-cell subpopulation sorting with high-throughput sequencing of the T-cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T-cell reconstitution after unrelated-donor hematopoietic stem cell transplant. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme B(high)/CD28(low)/CD57(high)/CD8(+) effector memory T cells (Tem) and resulted in a linked contraction of all naive T cells, including CD31(+)/CD4(+) putative thymic emigrants. T-cell receptor β (TCRβ) deep sequencing revealed a striking contraction of CD8(+) Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T-cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that, in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T-cell repertoire. This trial was registered at www.clinicaltrials.gov as #NCT01012492.

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

June 18, 2015

Volume

125

Issue

25

Start / End Page

3835 / 3850

Location

United States

Related Subject Headings

  • Young Adult
  • Virus Activation
  • Transplantation, Homologous
  • Receptors, Antigen, T-Cell, alpha-beta
  • Middle Aged
  • Male
  • Immunology
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Hematopoietic Stem Cell Transplantation
 

Citation

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Suessmuth, Y., Mukherjee, R., Watkins, B., Koura, D. T., Finstermeier, K., Desmarais, C., … Kean, L. S. (2015). CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire. Blood, 125(25), 3835–3850. https://doi.org/10.1182/blood-2015-03-631853
Suessmuth, Yvonne, Rithun Mukherjee, Benjamin Watkins, Divya T. Koura, Knut Finstermeier, Cindy Desmarais, Linda Stempora, et al. “CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire.Blood 125, no. 25 (June 18, 2015): 3835–50. https://doi.org/10.1182/blood-2015-03-631853.
Suessmuth Y, Mukherjee R, Watkins B, Koura DT, Finstermeier K, Desmarais C, et al. CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire. Blood. 2015 Jun 18;125(25):3835–50.
Suessmuth, Yvonne, et al. “CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire.Blood, vol. 125, no. 25, June 2015, pp. 3835–50. Pubmed, doi:10.1182/blood-2015-03-631853.
Suessmuth Y, Mukherjee R, Watkins B, Koura DT, Finstermeier K, Desmarais C, Stempora L, Horan JT, Langston A, Qayed M, Khoury HJ, Grizzle A, Cheeseman JA, Conger JA, Robertson J, Garrett A, Kirk AD, Waller EK, Blazar BR, Mehta AK, Robins HS, Kean LS. CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire. Blood. 2015 Jun 18;125(25):3835–3850.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

June 18, 2015

Volume

125

Issue

25

Start / End Page

3835 / 3850

Location

United States

Related Subject Headings

  • Young Adult
  • Virus Activation
  • Transplantation, Homologous
  • Receptors, Antigen, T-Cell, alpha-beta
  • Middle Aged
  • Male
  • Immunology
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Hematopoietic Stem Cell Transplantation