Blockade of CTLA-4 decreases the generation of multifunctional memory CD4+ T cells in vivo

Marion Rudolph, Katrin Hebel, Yoshinori Miyamura, Emanual Michael Maverakis, Monika C. Brunner-Weinzierl

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

CTLA-4 is known as a central inhibitor of T cell responses. It terminates T cell activation and proliferation and induces resistance against activation induced cell death. However, its impact on memory formation of adaptive immune responses is still unknown. In this study, we demonstrate that although anti-CTLA-4 mAb treatment during primary immunization of mice initially enhances the number of IFN-γ-producing CD4+ T cells, it does not affect the size of the memory pool. Interestingly, we find that the CTLA-4 blockade modulates the quality of the memory pool: it decreases the amount of specialized "multifunctional" memory CD4+ T cells coproducing IFN-γ, TNF-α, and IL-2 in response to Ag. The reduction of these cells causes an immense decrease of IFN-γ-producing T cells after in vivo antigenic rechallenge. Chimeric mice expressing CTLA-4-competent and -deficient cells unmask, which these CTLA-4-driven mechanisms are mediated CD4+ T cell nonautonomously. In addition, the depletion of CD25+ T cells prior to the generation of Ag-specific memory cells reveals that the constitutively CTLA-4-expressing natural regulatory T cells determine the quality of memory CD4+ T cells. Taken together, these results indicate that although the inhibitory molecule CTLA-4 damps the primary immune response, its engagement positively regulates the formation of a high-quality memory pool equipped with multifunctional CD4+ T cells capable of mounting a robust response to Ag rechallenge.

Original languageEnglish (US)
Pages (from-to)5580-5589
Number of pages10
JournalJournal of Immunology
Volume186
Issue number10
DOIs
StatePublished - May 15 2011

Fingerprint

T-Lymphocytes
Adaptive Immunity
Regulatory T-Lymphocytes
Interleukin-2
Immunization
Cell Death
Cell Proliferation

ASJC Scopus subject areas

  • Immunology

Cite this

Blockade of CTLA-4 decreases the generation of multifunctional memory CD4+ T cells in vivo. / Rudolph, Marion; Hebel, Katrin; Miyamura, Yoshinori; Maverakis, Emanual Michael; Brunner-Weinzierl, Monika C.

In: Journal of Immunology, Vol. 186, No. 10, 15.05.2011, p. 5580-5589.

Research output: Contribution to journalArticle

Rudolph, Marion ; Hebel, Katrin ; Miyamura, Yoshinori ; Maverakis, Emanual Michael ; Brunner-Weinzierl, Monika C. / Blockade of CTLA-4 decreases the generation of multifunctional memory CD4+ T cells in vivo. In: Journal of Immunology. 2011 ; Vol. 186, No. 10. pp. 5580-5589.
@article{3ba4a4aa68504fe5bc6f81e24364c074,
title = "Blockade of CTLA-4 decreases the generation of multifunctional memory CD4+ T cells in vivo",
abstract = "CTLA-4 is known as a central inhibitor of T cell responses. It terminates T cell activation and proliferation and induces resistance against activation induced cell death. However, its impact on memory formation of adaptive immune responses is still unknown. In this study, we demonstrate that although anti-CTLA-4 mAb treatment during primary immunization of mice initially enhances the number of IFN-γ-producing CD4+ T cells, it does not affect the size of the memory pool. Interestingly, we find that the CTLA-4 blockade modulates the quality of the memory pool: it decreases the amount of specialized {"}multifunctional{"} memory CD4+ T cells coproducing IFN-γ, TNF-α, and IL-2 in response to Ag. The reduction of these cells causes an immense decrease of IFN-γ-producing T cells after in vivo antigenic rechallenge. Chimeric mice expressing CTLA-4-competent and -deficient cells unmask, which these CTLA-4-driven mechanisms are mediated CD4+ T cell nonautonomously. In addition, the depletion of CD25+ T cells prior to the generation of Ag-specific memory cells reveals that the constitutively CTLA-4-expressing natural regulatory T cells determine the quality of memory CD4+ T cells. Taken together, these results indicate that although the inhibitory molecule CTLA-4 damps the primary immune response, its engagement positively regulates the formation of a high-quality memory pool equipped with multifunctional CD4+ T cells capable of mounting a robust response to Ag rechallenge.",
author = "Marion Rudolph and Katrin Hebel and Yoshinori Miyamura and Maverakis, {Emanual Michael} and Brunner-Weinzierl, {Monika C.}",
year = "2011",
month = "5",
day = "15",
doi = "10.4049/jimmunol.1003381",
language = "English (US)",
volume = "186",
pages = "5580--5589",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "10",

}

TY - JOUR

T1 - Blockade of CTLA-4 decreases the generation of multifunctional memory CD4+ T cells in vivo

AU - Rudolph, Marion

AU - Hebel, Katrin

AU - Miyamura, Yoshinori

AU - Maverakis, Emanual Michael

AU - Brunner-Weinzierl, Monika C.

PY - 2011/5/15

Y1 - 2011/5/15

N2 - CTLA-4 is known as a central inhibitor of T cell responses. It terminates T cell activation and proliferation and induces resistance against activation induced cell death. However, its impact on memory formation of adaptive immune responses is still unknown. In this study, we demonstrate that although anti-CTLA-4 mAb treatment during primary immunization of mice initially enhances the number of IFN-γ-producing CD4+ T cells, it does not affect the size of the memory pool. Interestingly, we find that the CTLA-4 blockade modulates the quality of the memory pool: it decreases the amount of specialized "multifunctional" memory CD4+ T cells coproducing IFN-γ, TNF-α, and IL-2 in response to Ag. The reduction of these cells causes an immense decrease of IFN-γ-producing T cells after in vivo antigenic rechallenge. Chimeric mice expressing CTLA-4-competent and -deficient cells unmask, which these CTLA-4-driven mechanisms are mediated CD4+ T cell nonautonomously. In addition, the depletion of CD25+ T cells prior to the generation of Ag-specific memory cells reveals that the constitutively CTLA-4-expressing natural regulatory T cells determine the quality of memory CD4+ T cells. Taken together, these results indicate that although the inhibitory molecule CTLA-4 damps the primary immune response, its engagement positively regulates the formation of a high-quality memory pool equipped with multifunctional CD4+ T cells capable of mounting a robust response to Ag rechallenge.

AB - CTLA-4 is known as a central inhibitor of T cell responses. It terminates T cell activation and proliferation and induces resistance against activation induced cell death. However, its impact on memory formation of adaptive immune responses is still unknown. In this study, we demonstrate that although anti-CTLA-4 mAb treatment during primary immunization of mice initially enhances the number of IFN-γ-producing CD4+ T cells, it does not affect the size of the memory pool. Interestingly, we find that the CTLA-4 blockade modulates the quality of the memory pool: it decreases the amount of specialized "multifunctional" memory CD4+ T cells coproducing IFN-γ, TNF-α, and IL-2 in response to Ag. The reduction of these cells causes an immense decrease of IFN-γ-producing T cells after in vivo antigenic rechallenge. Chimeric mice expressing CTLA-4-competent and -deficient cells unmask, which these CTLA-4-driven mechanisms are mediated CD4+ T cell nonautonomously. In addition, the depletion of CD25+ T cells prior to the generation of Ag-specific memory cells reveals that the constitutively CTLA-4-expressing natural regulatory T cells determine the quality of memory CD4+ T cells. Taken together, these results indicate that although the inhibitory molecule CTLA-4 damps the primary immune response, its engagement positively regulates the formation of a high-quality memory pool equipped with multifunctional CD4+ T cells capable of mounting a robust response to Ag rechallenge.

UR - http://www.scopus.com/inward/record.url?scp=79956215089&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79956215089&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1003381

DO - 10.4049/jimmunol.1003381

M3 - Article

C2 - 21478403

AN - SCOPUS:79956215089

VL - 186

SP - 5580

EP - 5589

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 10

ER -