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Toso regulates differentiation and activation of inflammatory dendritic cells during persistence-prone virus infection.

ABSTRACT: During virus infection and autoimmune disease, inflammatory dendritic cells (iDCs) differentiate from blood monocytes and infiltrate infected tissue. Following acute infection with hepatotropic viruses, iDCs are essential for re-stimulating virus-specific CD8(+) T cells and therefore contribute to virus control. Here we used the lymphocytic choriomeningitis virus (LCMV) model system to identify novel signals, which influence the recruitment and activation of iDCs in the liver. We observed that intrinsic expression of Toso (Faim3, Fc?R) influenced the differentiation and activation of iDCs in vivo and DCs in vitro. Lack of iDCs in Toso-deficient (Toso(-/-)) mice reduced CD8(+) T-cell function in the liver and resulted in virus persistence. Furthermore, Toso(-/-) DCs failed to induce autoimmune diabetes in the rat insulin promoter-glycoprotein (RIP-GP) autoimmune diabetes model. In conclusion, we found that Toso has an essential role in the differentiation and maturation of iDCs, a process that is required for the control of persistence-prone virus infection.

SUBMITTER: Lang PA

PROVIDER: S-EPMC4262783 | biostudies-other | 2015 Jan

REPOSITORIES: biostudies-other

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Toso regulates differentiation and activation of inflammatory dendritic cells during persistence-prone virus infection.

Lang P A PA Meryk A A Pandyra A A AA Brenner D D Brüstle A A Xu H C HC Merches K K Lang F F Khairnar V V Sharma P P Funkner P P Recher M M Shaabani N N Duncan G S GS Duhan V V Homey B B Ohashi P S PS Häussinger D D Knolle P A PA Honke N N Mak T W TW Lang K S KS

Cell death and differentiation 20140926 1

During virus infection and autoimmune disease, inflammatory dendritic cells (iDCs) differentiate from blood monocytes and infiltrate infected tissue. Following acute infection with hepatotropic viruses, iDCs are essential for re-stimulating virus-specific CD8(+) T cells and therefore contribute to virus control. Here we used the lymphocytic choriomeningitis virus (LCMV) model system to identify novel signals, which influence the recruitment and activation of iDCs in the liver. We observed that i ...[more]

PMID: 25257173

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Project description:Targeted HIV cure strategies require definition of the mechanisms that maintain the virus. Here, we tracked HIV replication and the persistence of infected CD4 T cells in individuals with natural virologic control by sequencing viruses, T cell receptor genes, HIV integration sites and cellular transcriptomes. Our results revealed three mechanisms of HIV persistence operating within distinct anatomic and functional compartments. In lymph node, we detected viruses with genetic and transcriptional attributes of active replication in both T follicular helper (TFH) cells and non-TFH memory cells. In blood, we detected inducible proviruses of archival origin among highly differentiated, clonally expanded cells. Linking the lymph node and blood was a small population of circulating cells harboring inducible proviruses of recent origin. Thus, HIV replication in lymphoid tissue, clonal expansion of infected cells, and recirculation of recently infected cells act together to maintain the virus in HIV controllers despite effective antiviral immunity. Fluorescence-activated cell sorting (FACS) was used to sort subsets of CD4 T cells from blood (peripheral blood mononuclear cells; PBMC) and lymph node from a cohort of HIV-infected people with natural control of the virus (termed HIV controllers). Subsets of CD4 T cells that were sorted are as follows: from blood, (1) naÃ¯ve (N), (2) central memory (CM), (3) transitional memory (TM), and (4) effector memory (EM); from lymph node, (1) naÃ¯ve (N), (2) non-germinal center T-follicular helpers (nGC), (3) germinal center T-follicular helpers (Tfh), (4) effector memory (EM), and (5) other central memory-like subsets (CMPD1lo57lo, CMPD1lo57hi, and/or CMPD1lo). Total RNA and total DNA were extracted from these sorted subsets in separate fractions using RNAzol RT and DNAzol. Total cellular DNA was used for HIV quantification and sequence analysis as describe in the publication. Total RNA used for mRNA library construction by oligo-dT purification (Dynabeads), random fragmentation by heating in the presence of Magnesium (in form of 5x first-strand buffer, LifeTech), reverse transcription (SuperScript III), and then second-strand synthesis, end repair, a-tailing, and adaptor ligation using NEBNext enzyme master mixes and oligonucleotides. Libraries were sequenced on an Illumina HiSeq2000. Please note that each 'source name' value represent individual who havs HIV infection with natural control of the virus.

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Toso regulates differentiation and activation of inflammatory dendritic cells during persistence-prone virus infection.

Publications

Toso regulates differentiation and activation of inflammatory dendritic cells during persistence-prone virus infection.

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