Dataset Information

M(IL-4) Tissue Macrophages Support Efficient Interferon-Gamma Production in Antigen-Specific CD8+ T Cells with Reduced Proliferative Capacity.

ABSTRACT: CD8+ cytotoxic T cell (CTL) responses are necessary for the lysis of virally infected cells and control of infection. CTLs are activated when their TCRs bind a major histocompatibility complex (MHC)-I/peptide complex on the surface of antigen presenting cells such as macrophages (M?). It is now apparent that M? display remarkable plasticity in response to environmental signals to polarize into classically activated M(LPS?+?IFN-?) or alternatively activated M(IL-4). However, little is known about how M? activation status influences their antigen presentation function to CD8+ T cell in models of virus infection. Consequently, we tested how polarization of spleen-derived (Sp)-M? impacts direct presentation of viral antigens to influence effector and proliferative CD8+ T-cell responses. We show that M(IL-4) Sp-M? retain MHC-I surface expression and the ability to stimulate IFN-? production by CTL following peptide stimulation and lymphocytic choriomeningitis virus infection to levels similar to M0 and M(LPS?+?IFN-?) M?. However, memory CD8+ T cells cultured in the presence of M(IL-4) M? underwent significantly reduced proliferation and produced similar IFN-? levels as coculturing with M0 or M(LPS?+?IFN-?) cells. Thus, these results show a novel ability of polarized M? to regulate CD8+ T-cell proliferation and effector functions during virus infection.

SUBMITTER: Mulder R

PROVIDER: S-EPMC5714867 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

M(IL-4) Tissue Macrophages Support Efficient Interferon-Gamma Production in Antigen-Specific CD8<sup>+</sup> T Cells with Reduced Proliferative Capacity.

Mulder Rylend R Banete Andra A Seaver Kyle K Basta Sameh S

Frontiers in immunology 20171130

CD8<sup>+</sup> cytotoxic T cell (CTL) responses are necessary for the lysis of virally infected cells and control of infection. CTLs are activated when their TCRs bind a major histocompatibility complex (MHC)-I/peptide complex on the surface of antigen presenting cells such as macrophages (MΦ). It is now apparent that MΦ display remarkable plasticity in response to environmental signals to polarize into classically activated M(LPS + IFN-γ) or alternatively activated M(IL-4). However, little is ...[more]

PMID: 29250063

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Project description:Interleukin-15 (IL-15) is a cytokine that has been shown to expand CD8 T cell and natural killer (NK) cell populations, and therefore has potential for potentiating adoptive immune cell therapy for cancer. Previously, IL-15 has been shown to induce proliferation of CD8 memory T cells through activation of telomerase. Here, we investigated whether telomerase is also activated during the IL-15 mediated proliferation of NK and NKT-like (CD56+CD3+) cells. We also examined the extent that each of the three signaling pathways known to be stimulated by IL-2/IL-15 (JAK-STAT, PI3K-AKT Ras-RAF/MAPK) were activated and involved in the telomerase expression in the three cell types NK, NKT, or CD8 T cells. To assess cell proliferation and doubling, peripheral blood mononuclear cells (PBMCs) or isolated NK, NKT-like or CD8 T cells were incubated with varying concentrations of IL-15 or IL-2 for 7 days. CD8 T, NK, and NKT cell expansion was determined by fluorophore-conjugated antibody staining and flow cytometry. Cell doubling was investigated using carboxyfluorescein-succinimidyl-ester (CFSE). Telomerase expression was investigated by staining cells with anti-telomerase reverse transcriptase (anti-TERT). Telomerase activity in CD56+ and CD8 T cells was also measured via Telomerase Repeat Amplification Protocol (TRAP). Analysis of cellular expansion, proliferation and TERT expression concluded that IL-15 increased cellular growth of NK, NKT, and CD8 T cells more effectively than IL-2 using low or high doses. IL-15, increased TERT expression in NK and NKT cells by up to 2.5 fold, the same increase seen in CD8 T cells. IL-2 had effects on TERT expression only at high doses (100-1000 ng/ml). Proteome profiling identified that IL-15 activated selected signaling proteins in the three pathways (JAK-STAT, PI3K-AKT, Ras-MAPK) known to mediate IL-2/IL-15 signaling, more strongly than IL-2. Evaluation by signaling pathway inhibitors revealed that JAK/STAT and PI3K/AKT pathways are important in IL-15's ability to upregulate TERT expression in NK and NKT cells, whereas all three pathways were involved in CD8 T cell TERT expression. In conclusion, this study shows that IL-15 potently stimulates TERT upregulation in NK and NKT cells in addition to CD8 T cells and is therefore a valuable tool for adoptive cell therapies.

Dataset Information

M(IL-4) Tissue Macrophages Support Efficient Interferon-Gamma Production in Antigen-Specific CD8+ T Cells with Reduced Proliferative Capacity.

Publications

M(IL-4) Tissue Macrophages Support Efficient Interferon-Gamma Production in Antigen-Specific CD8<sup>+</sup> T Cells with Reduced Proliferative Capacity.

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