Manipulating Memory CD8 T Cell Numbers by Timed Enhancement of IL-2 Signals

Marie T Kim; Samarchith P Kurup; Gabriel R Starbeck-Miller; John T Harty

doi:10.4049/jimmunol.1600641

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Manipulating Memory CD8 T Cell Numbers by Timed Enhancement of IL-2 Signals

Journal article

Peer reviewed

Manipulating Memory CD8 T Cell Numbers by Timed Enhancement of IL-2 Signals

Marie T Kim, Samarchith P Kurup, Gabriel R Starbeck-Miller and John T Harty

The Journal of immunology (1950), Vol.197(5), pp.1754-1761

09/01/2016

DOI: 10.4049/jimmunol.1600641

PMCID: PMC4992593

PMID: 27439516

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Abstract

As a result of the growing burden of tumors and chronic infections, manipulating CD8 T cell responses for clinical use has become an important goal for immunologists. In this article, we show that dendritic cell (DC) immunization coupled with relatively early (days 1-3) or late (days 4-6) administration of enhanced IL-2 signals increase peak effector CD8 T cell numbers, but only early IL-2 signals enhance memory numbers. IL-2 signals delivered at relatively late time points drive terminal differentiation and marked Bim-mediated contraction and do not increase memory T cell numbers. In contrast, early IL-2 signals induce effector cell metabolic profiles that are more conducive to memory formation. Of note, downregulation of CD80 and CD86 was observed on DCs in vivo following early IL-2 treatment. Mechanistically, early IL-2 treatment enhanced CTLA-4 expression on regulatory T cells, and CTLA-4 blockade alongside IL-2 treatment in vivo prevented the decrease in CD80 and CD86, supporting a cell-extrinsic role for CTLA-4 in downregulating B7 ligand expression on DCs. Finally, DC immunization followed by early IL-2 treatment and anti-CTLA-4 blockade resulted in lower memory CD8 T cell numbers compared with the DC+early IL-2 treatment group. These data suggest that curtailed signaling through the B7-CD28 costimulatory axis during CD8 T cell activation limits terminal differentiation and preserves memory CD8 T cell formation; thus, it should be considered in future T cell-vaccination strategies.

Interleukin-2 - metabolism

Immunization

B7-1 Antigen - genetics

Signal Transduction

B7-1 Antigen - immunology

Lymphocyte Activation

Cell Count

Dendritic Cells - immunology

Down-Regulation

CTLA-4 Antigen - genetics

B7 Antigens - immunology

CD28 Antigens - immunology

CTLA-4 Antigen - immunology

CD28 Antigens - metabolism

T-Lymphocytes, Regulatory - immunology

Animals

Interleukin-2 - immunology

Time Factors

B7 Antigens - genetics

Immunologic Memory

Mice

B7-2 Antigen - immunology

CD8-Positive T-Lymphocytes - immunology

Details

Title: Subtitle: Manipulating Memory CD8 T Cell Numbers by Timed Enhancement of IL-2 Signals
Creators: Marie T Kim - Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242; Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Samarchith P Kurup - Department of Microbiology, University of Iowa, Iowa City, IA 52242; and
Gabriel R Starbeck-Miller - Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242
John T Harty - Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242; Department of Microbiology, University of Iowa, Iowa City, IA 52242; and Department of Pathology, University of Iowa, Iowa City, IA 52242 john-harty@uiowa.edu
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.197(5), pp.1754-1761
DOI: 10.4049/jimmunol.1600641
PMID: 27439516
PMCID: PMC4992593
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: United States
Grant note: R01 AI042767 / NIAID NIH HHS R37 AI042767 / NIAID NIH HHS T32 AI007485 / NIAID NIH HHS T32 GM007337 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 09/01/2016
Academic Unit: Microbiology and Immunology; Pathology
Record Identifier: 9984047976502771

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