Gel-Trapped Lymphorganogenic Chemokines Trigger Artificial Tertiary Lymphoid Organs and Mount Adaptive Immune Responses In Vivo

ABSTRACT Helper-dependent adenovirus (HD-Ad) vectors with all adenoviral genes deleted mediate very long-term expression of therapeutic transgenes in a variety of animal models of disease. These vectors are associated with reduced toxicity and improved safety relative to traditional early region 1 deletion first-generation Ad (FG-Ad) vectors. Many studies have clearly demonstrated that FG-Ad vectors induce innate and adaptive immune responses in vivo; however, a comprehensive analysis of host immune responses to HD-Ad vectors has not yet been performed. In DBA/2 mice, intravenous injection of HD-Ad vectors encoding LacZ (HD-AdLacZ) or a murine secreted alkaline phosphatase (HD-AdSEAP) induced an early expression of inflammatory cytokine and chemokine genes in the liver, including interferon-inducible protein 10, macrophage inflammatory protein 2, and tumor necrosis factor alpha, and were expressed in a pattern similar to that induced by FG-Ad vectors encoding AdSEAP. Like AdSEAP, and consistent with the pattern of cellular gene expression, HD-AdLacZ and HD-AdSEAP induced the recruitment of CD11b-positive leukocytes to the transduced liver within hours of administration. AdSEAP also induced a second phase of liver inflammation, consisting of inflammatory gene expression and CD3-positive lymphocytic infiltrates 7 days posttransduction. In contrast, beyond 24 h no infiltrates or expression of inflammatory genes was detected in the livers of mice receiving HD-AdSEAP. Despite the lack of liver inflammation at 7 days, Ad-specific cytotoxic T lymphocytes could be detected in mice receiving HD-AdSEAP. This lack of liver inflammation was not due to reduced transduction since levels of transgene expression and the amounts of vector DNA in the liver were equivalent in mice receiving HD-AdSEAP and AdSEAP. These results demonstrate that HD-Ad vectors induce intact innate but attenuated adaptive immune responses in vivo.

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Artery Tertiary Lymphoid Organs Contribute to Innate and Adaptive Immune Responses in Advanced Mouse Atherosclerosis

Circulation Research ◽

10.1161/circresaha.114.301137 ◽

2014 ◽

Vol 114 (11) ◽

pp. 1772-1787 ◽

Cited By ~ 58

Author(s):

Sarajo Kumar Mohanta ◽

Changjun Yin ◽

Li Peng ◽

Prasad Srikakulapu ◽

Vineela Bontha ◽

...

Keyword(s):

Immune Responses ◽

Lymphoid Organs ◽

Adaptive Immune Responses ◽

Adaptive Immune

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Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions

Journal of Experimental Medicine ◽

10.1084/jem.20091925 ◽

2009 ◽

Vol 206 (13) ◽

pp. 3101-3114 ◽

Cited By ~ 475

Author(s):

Olga Schulz ◽

Elin Jaensson ◽

Emma K. Persson ◽

Xiaosun Liu ◽

Tim Worbs ◽

...

Keyword(s):

Immune Responses ◽

Direct Injection ◽

Turnover Rates ◽

Mesenteric Lymph Nodes ◽

Adaptive Immune Responses ◽

Cell Functions ◽

Adaptive Immune ◽

Inflammatory Conditions

Chemokine receptor CX3CR1+ dendritic cells (DCs) have been suggested to sample intestinal antigens by extending transepithelial dendrites into the gut lumen. Other studies identified CD103+ DCs in the mucosa, which, through their ability to synthesize retinoic acid (RA), appear to be capable of generating typical signatures of intestinal adaptive immune responses. We report that CD103 and CX3CR1 phenotypically and functionally characterize distinct subsets of lamina propria cells. In contrast to CD103+ DC, CX3CR1+ cells represent a nonmigratory gut-resident population with slow turnover rates and poor responses to FLT-3L and granulocyte/macrophage colony-stimulating factor. Direct visualization of cells in lymph vessels and flow cytometry of mouse intestinal lymph revealed that CD103+ DCs, but not CX3CR1-expressing cells, migrate into the gut draining mesenteric lymph nodes (LNs) under steady-state and inflammatory conditions. Moreover, CX3CR1+ cells displayed poor T cell stimulatory capacity in vitro and in vivo after direct injection of cells into intestinal lymphatics and appeared to be less efficient at generating RA compared with CD103+ DC. These findings indicate that selectively CD103+ DCs serve classical DC functions and initiate adaptive immune responses in local LNs, whereas CX3CR1+ populations might modulate immune responses directly in the mucosa and serve as first line barrier against invading enteropathogens.

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619. AAV Vector-Mediated Activation of Canonical and Alternative NF-κβ Pathways In Vivo: Implications for Innate and Adaptive Immune Responses and Gene Therapy

Molecular Therapy ◽

10.1016/s1525-0016(16)37192-1 ◽

2011 ◽

Vol 19 ◽

pp. S237-S238

Keyword(s):

Gene Therapy ◽

Immune Responses ◽

Adaptive Immune Responses ◽

Aav Vector ◽

Adaptive Immune

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Macrophage-specific MHCII expression is regulated by a remote Ciita enhancer controlled by NFAT5

Journal of Experimental Medicine ◽

10.1084/jem.20180314 ◽

2018 ◽

Vol 215 (11) ◽

pp. 2901-2918 ◽

Cited By ~ 13

Author(s):

Maria Buxadé ◽

Hector Huerga Encabo ◽

Marta Riera-Borrull ◽

Lucía Quintana-Gallardo ◽

Pilar López-Cotarelo ◽

...

Keyword(s):

Transcription Factor ◽

Immune Responses ◽

T Lymphocyte ◽

Cell Type ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Cell Type Specific ◽

Antigen Presenting ◽

Mhcii Expression

MHCII in antigen-presenting cells (APCs) is a key regulator of adaptive immune responses. Expression of MHCII genes is controlled by the transcription coactivator CIITA, itself regulated through cell type–specific promoters. Here we show that the transcription factor NFAT5 is needed for expression of Ciita and MHCII in macrophages, but not in dendritic cells and other APCs. NFAT5-deficient macrophages showed defective activation of MHCII-dependent responses in CD4+ T lymphocytes and attenuated capacity to elicit graft rejection in vivo. Ultrasequencing analysis of NFAT5-immunoprecipitated chromatin uncovered an NFAT5-regulated region distally upstream of Ciita. This region was required for CIITA and hence MHCII expression, exhibited NFAT5-dependent characteristics of active enhancers such as H3K27 acetylation marks, and required NFAT5 to interact with Ciita myeloid promoter I. Our results uncover an NFAT5-regulated mechanism that maintains CIITA and MHCII expression in macrophages and thus modulates their T lymphocyte priming capacity.

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Undaria pinnatifida Fucoidan-Rich Extract Induces Both Innate and Adaptive Immune Responses

Natural Product Communications ◽

10.1177/1934578x19873724 ◽

2019 ◽

Vol 14 (8) ◽

pp. 1934578X1987372

Author(s):

Hwan H. Lee ◽

Yoo J. Cho ◽

Daeung Yu ◽

Donghwa Chung ◽

Gun-Hee Kim ◽

...

Keyword(s):

Immune Responses ◽

Cd8 T Cells ◽

Undaria Pinnatifida ◽

Plasma Concentrations ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Tnf Α ◽

Ifn Γ

Fucoidans are widely used as an ingredient of dietary supplements. We investigated the immune stimulatory activities of Undaria pinnatifida ( Alariaceae) fucoidan-rich extract (UPF-RE) in vitro as well as in vivo . In vitro, the extract stimulated Raw 264.7 cells to produce significant nitric oxide (NO) metabolites and cytokines (TNF-α, IL-1α, IL-1β, and IL-6). It also induced the proliferation of primary mouse splenocytes and the secretion of IL-4, which correlated with the phosphorylation of Extracellular-signal-regulated kinase (ERK) protein. In in vivo experiments, first, 50 mg/kg of 3 different types of UPF-RE, DSU02, DSU02L (low molecular weight, <3 kDa), and DSU02H (high molecular weight, >10 kDa), were orally administered to C57BL/6 mice. After 14 days, the frequencies of CD3+, CD4+, and CD8+ T cells and NK cells from each group were analyzed. Plasma concentrations of TNF-α and IFN-γ were determined. The frequencies of CD3+ and CD4+ showed a statistically significant increase in splenocytes isolated from the DSU02 and DSU02H groups. Also, there was significant production of TNF-α and IFN-γ from the DSU02 group. Second, 3 different concentrations of DSU02 (50, 100, and 150 mg/kg) were orally administered. After 14 days, the proliferative capacity of CD3+, CD4+, and CD8+ T cells was investigated, and the plasma concentrations of IgM and total IgG were determined. Plasma concentration of IgM from the DSU02 150 mg/kg group was statistically significantly higher compared with that from the other groups. We suggest that UPF-RE could be a good candidate for a natural immune stimulator to induce innate as well as adaptive immune responses.

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