title: LPS stimulates and Hsp70 down-regulates TLR4 to orchestrate differential cytokine response of culture-differentiated innate memory CD8(+) T cells.
abstract: Nonconventional innate memory CD8(+) T cells characteristically expressing CD44, CD122, eomesodermin (Eomes) and promyelocytic leukemia zinc finger (PLZF) were derived in culture from CD4(+)CD8(+) double positive (DP) thymocytes of normal BALB/c and C57BL/6 mice. These culture-differentiated cells constitutively express toll-like receptor (TLR)4 and release interferon (IFN)-γ and interleukin (IL)-10. We show the TLR4-ligand lipopolysaccharide (LPS) stimulate the TLR and up-regulate IFN-γ skewing the cells towards type 1 polarization. In presence of LPS these cells also express suppressor of cytokine signaling (SOCS)1 and thus suppress IL-10 expression. In contrast, heat shock protein (Hsp)70 down-regulated TLR4 augmenting the anti-inflammatory cytokine IL-10. In association with IL-10 release IFN-γ was abrogated. The programmed cell death (PD)-1 mostly present in regulatory T cells was stimulated in these IL-10 producing cells by Hsp70 and not LPS indicating the cells can be driven to two contrast outcomes by the two TLR4 ligands. Our work provides a scope for in vitro monitoring of CD8(+) T cells to decipher important immune therapeutic option during infection or sepsis.
authors.affiliation: Division of Immunology, National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Amlan Kanti
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: Division of Immunology, National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Debolina
authors.initials: D
authors.lastname: Sinha
authors.affiliation: Division of Immunology, National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Subhadeep
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Division of Immunology, National Institute of Cholera and Enteric Diseases, Kolkata, India. Electronic address: immuneprolactin@yahoo.co.in.
authors.forename: Ratna
authors.initials: R
authors.lastname: Biswas
authors.affiliation: Division of Immunology, National Institute of Cholera and Enteric Diseases, Kolkata, India. Electronic address: shigellaporin@yahoo.com.
authors.forename: Tapas
authors.initials: T
authors.lastname: Biswas
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005434:Flow Cytometry; D018840:HSP70 Heat-Shock Proteins / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007156:Immunologic Memory / Q000187:drug effects; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051197:Toll-Like Receptor 4; C485837:Tollip protein, mouse; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: CD4(+)CD8(+) thymocyte; Cytokines; Differentiation; Innate immunity; Pattern recognition receptor