Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation

Ken-ichi Matsuoka, Haesook T. Kim, Sean McDonough, Gregory Bascug, Ben Warshauer, John Koreth, Corey Cutler, Vincent T. Ho, Edwin P. Alyea, Joseph H. Antin, Robert J. Soiffer, Jerome Ritz

Research output: Contribution to journalArticle

139 Citations (Scopus)

Abstract

CD4+CD25+Foxp3+ Tregs have an indispensable role in the maintenance of tolerance after allogeneic HSC transplantation (HSCT). Patients with chronic graft-versus-host disease (GVHD) have fewer circulating Tregs, but the mechanisms that lead to this deficiency of Tregs after HSCT are not known. Here, we analyzed reconstitution of Tregs and conventional CD4+ T cells (Tcons) in patients who underwent allogeneic HSCT after myeloablative conditioning. Following transplant, thymic generation of naive Tregs was markedly impaired, and reconstituting Tregs had a predominantly activated/memory phenotype. In response to CD4+ lymphopenia after HSCT, Tregs underwent higher levels of proliferation than Tcons, but Tregs undergoing homeostatic proliferation also showed increased susceptibility to Fas-mediated apoptosis. Prospective monitoring of CD4 + T cell subsets revealed that Tregs rapidly expanded and achieved normal levels by 9 months after HSCT, but Treg levels subsequently declined in patients with prolonged CD4+ lymphopenia. This resulted in a relative deficiency of Tregs, which was associated with a high incidence of extensive chronic GVHD. These studies indicate that CD4+ lymphopenia is a critical factor in Treg homeostasis and that prolonged imbalance of Treg homeostasis after HSCT can result in loss of tolerance and significant clinical disease manifestations.

Original languageEnglish
Pages (from-to)1479-1493
Number of pages15
JournalJournal of Clinical Investigation
Volume120
Issue number5
DOIs
Publication statusPublished - May 3 2010
Externally publishedYes

Fingerprint

Lymphopenia
Hematopoietic Stem Cell Transplantation
Regulatory T-Lymphocytes
Homeostasis
Transplantation
Homologous Transplantation
Graft vs Host Disease
T-Lymphocyte Subsets
Maintenance
Apoptosis
T-Lymphocytes
Transplants
Phenotype
Incidence

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation. / Matsuoka, Ken-ichi; Kim, Haesook T.; McDonough, Sean; Bascug, Gregory; Warshauer, Ben; Koreth, John; Cutler, Corey; Ho, Vincent T.; Alyea, Edwin P.; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jerome.

In: Journal of Clinical Investigation, Vol. 120, No. 5, 03.05.2010, p. 1479-1493.

Research output: Contribution to journalArticle

Matsuoka, K, Kim, HT, McDonough, S, Bascug, G, Warshauer, B, Koreth, J, Cutler, C, Ho, VT, Alyea, EP, Antin, JH, Soiffer, RJ & Ritz, J 2010, 'Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation', Journal of Clinical Investigation, vol. 120, no. 5, pp. 1479-1493. https://doi.org/10.1172/JCI41072
Matsuoka, Ken-ichi ; Kim, Haesook T. ; McDonough, Sean ; Bascug, Gregory ; Warshauer, Ben ; Koreth, John ; Cutler, Corey ; Ho, Vincent T. ; Alyea, Edwin P. ; Antin, Joseph H. ; Soiffer, Robert J. ; Ritz, Jerome. / Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 5. pp. 1479-1493.
@article{8ced2b63d2674f68a3079208d3e932cd,
title = "Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation",
abstract = "CD4+CD25+Foxp3+ Tregs have an indispensable role in the maintenance of tolerance after allogeneic HSC transplantation (HSCT). Patients with chronic graft-versus-host disease (GVHD) have fewer circulating Tregs, but the mechanisms that lead to this deficiency of Tregs after HSCT are not known. Here, we analyzed reconstitution of Tregs and conventional CD4+ T cells (Tcons) in patients who underwent allogeneic HSCT after myeloablative conditioning. Following transplant, thymic generation of naive Tregs was markedly impaired, and reconstituting Tregs had a predominantly activated/memory phenotype. In response to CD4+ lymphopenia after HSCT, Tregs underwent higher levels of proliferation than Tcons, but Tregs undergoing homeostatic proliferation also showed increased susceptibility to Fas-mediated apoptosis. Prospective monitoring of CD4 + T cell subsets revealed that Tregs rapidly expanded and achieved normal levels by 9 months after HSCT, but Treg levels subsequently declined in patients with prolonged CD4+ lymphopenia. This resulted in a relative deficiency of Tregs, which was associated with a high incidence of extensive chronic GVHD. These studies indicate that CD4+ lymphopenia is a critical factor in Treg homeostasis and that prolonged imbalance of Treg homeostasis after HSCT can result in loss of tolerance and significant clinical disease manifestations.",
author = "Ken-ichi Matsuoka and Kim, {Haesook T.} and Sean McDonough and Gregory Bascug and Ben Warshauer and John Koreth and Corey Cutler and Ho, {Vincent T.} and Alyea, {Edwin P.} and Antin, {Joseph H.} and Soiffer, {Robert J.} and Jerome Ritz",
year = "2010",
month = "5",
day = "3",
doi = "10.1172/JCI41072",
language = "English",
volume = "120",
pages = "1479--1493",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation

AU - Matsuoka, Ken-ichi

AU - Kim, Haesook T.

AU - McDonough, Sean

AU - Bascug, Gregory

AU - Warshauer, Ben

AU - Koreth, John

AU - Cutler, Corey

AU - Ho, Vincent T.

AU - Alyea, Edwin P.

AU - Antin, Joseph H.

AU - Soiffer, Robert J.

AU - Ritz, Jerome

PY - 2010/5/3

Y1 - 2010/5/3

N2 - CD4+CD25+Foxp3+ Tregs have an indispensable role in the maintenance of tolerance after allogeneic HSC transplantation (HSCT). Patients with chronic graft-versus-host disease (GVHD) have fewer circulating Tregs, but the mechanisms that lead to this deficiency of Tregs after HSCT are not known. Here, we analyzed reconstitution of Tregs and conventional CD4+ T cells (Tcons) in patients who underwent allogeneic HSCT after myeloablative conditioning. Following transplant, thymic generation of naive Tregs was markedly impaired, and reconstituting Tregs had a predominantly activated/memory phenotype. In response to CD4+ lymphopenia after HSCT, Tregs underwent higher levels of proliferation than Tcons, but Tregs undergoing homeostatic proliferation also showed increased susceptibility to Fas-mediated apoptosis. Prospective monitoring of CD4 + T cell subsets revealed that Tregs rapidly expanded and achieved normal levels by 9 months after HSCT, but Treg levels subsequently declined in patients with prolonged CD4+ lymphopenia. This resulted in a relative deficiency of Tregs, which was associated with a high incidence of extensive chronic GVHD. These studies indicate that CD4+ lymphopenia is a critical factor in Treg homeostasis and that prolonged imbalance of Treg homeostasis after HSCT can result in loss of tolerance and significant clinical disease manifestations.

AB - CD4+CD25+Foxp3+ Tregs have an indispensable role in the maintenance of tolerance after allogeneic HSC transplantation (HSCT). Patients with chronic graft-versus-host disease (GVHD) have fewer circulating Tregs, but the mechanisms that lead to this deficiency of Tregs after HSCT are not known. Here, we analyzed reconstitution of Tregs and conventional CD4+ T cells (Tcons) in patients who underwent allogeneic HSCT after myeloablative conditioning. Following transplant, thymic generation of naive Tregs was markedly impaired, and reconstituting Tregs had a predominantly activated/memory phenotype. In response to CD4+ lymphopenia after HSCT, Tregs underwent higher levels of proliferation than Tcons, but Tregs undergoing homeostatic proliferation also showed increased susceptibility to Fas-mediated apoptosis. Prospective monitoring of CD4 + T cell subsets revealed that Tregs rapidly expanded and achieved normal levels by 9 months after HSCT, but Treg levels subsequently declined in patients with prolonged CD4+ lymphopenia. This resulted in a relative deficiency of Tregs, which was associated with a high incidence of extensive chronic GVHD. These studies indicate that CD4+ lymphopenia is a critical factor in Treg homeostasis and that prolonged imbalance of Treg homeostasis after HSCT can result in loss of tolerance and significant clinical disease manifestations.

UR - http://www.scopus.com/inward/record.url?scp=77951870520&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951870520&partnerID=8YFLogxK

U2 - 10.1172/JCI41072

DO - 10.1172/JCI41072

M3 - Article

VL - 120

SP - 1479

EP - 1493

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -