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 language | English (US) |
|---|---|
| Pages (from-to) | 5580-5589 |
| Number of pages | 10 |
| Journal | Journal of Immunology |
| Volume | 186 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 15 2011 |
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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 journal › Article
}
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.
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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 -