Unknown,Transcriptomics,Genomics,Proteomics

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A Temporal Switch in the Germinal Center Determines Differential Output of Memory B and Plasma Cells

ABSTRACT: There is little insight into or agreement about the signals that control differentiation of memory B cells (MBC) and long-lived plasma cells (LLPC). By performing BrdU pulse-labeling studies, we found that MBC formation preceded the formation of LLPC in an adoptive transfer immunization system, which allowed for a synchronized Ag-specific response with homogeneous Ag-receptor, yet at natural precursor frequencies. We confirmed observations in wild type (WT) mice and extended them with germinal center (GC) disruption experiments and variable region gene sequencing. We thus show that the GC response undergo a temporal switch in its output as it matures, revealing that the reaction engenders both MBC subsets with different immune effector function and, ultimately, LLPC at largely separate points in time. These data demonstrate the kinetics of the formation of the cells that provide stable humoral immunity and therefore have implications for autoimmunity, vaccine development, and for understanding long-term pathogen resistance. Adoptive transfer of B1-8i+/- genetically targeted BALB/cJ mice B cells into AM14 Transgenic (Tg) x VÎº8R genetically targeted BALB/cJ mice. Naive, memory, early and late GC B cells.

ORGANISM(S): Mus musculus

SUBMITTER: Maria Chikina

PROVIDER: E-GEOD-76502 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The optimal T cell attributes for the adoptive immunotherapy of cancer and viral diseases are currently unclear. Recent adoptive transfer clinical trials using ex vivo expanded tumor infiltrating lymphocytes has provided evidence that differentiated effector T cells can mediate durable responses in selected cancer patients. The capacity of these transferred cells to persist in the host was found to strongly correlate with their clinical activity. Thus, there is significant interest in identifying intrinsic markers that define antigen specific effector T cells that can develop into long-lived memory cells rather than undergoing apoptosis after infusion in humans. We recently reported the long term persistence of ex vivo expanded tumor specific CD8+ T effector clones in refractory metastatic melanoma patients after adoptive T cell transfer. By utilizing these highly homogeneous clone populations, we sought to define the pre-infusion cellular and molecular attributes associated with their effector to memory transition. Comparative transcriptional profiling found the pre-infusion clone mRNA expression levels of the IL-7 receptor (IL-7Ra) and the proto-oncogene, c-myc, directly correlated with the level of clonal persistence after adoptive transfer in humans. The predictive value of these markers was further established by utilizing IL-7R protein, induced pSTAT5, and c-myc mRNA expression to prospectively identify human tumor specific effector clones that could engraft after controlled adoptive transfer into highly immunodeficient mice. These findings support that IL-7R and c-myc expression are valuable cell intrinsic markers that can predict the fate of effector CD8+ T cells after adoptive transfer. We used microarrays to compare the pre-infusion gene expression profile of melanoma-specific CD8+ T cell clones that would eventually either persist or not after adoptive transfer in humans. We derived ten melanoma-specific CD8+ T cell clones and determined their degree of persistence after adoptive therapy into patients. We performed microarray on the pre-infusion samples of six persisting and four non-persisting clones to obtain a comparative gene signature profile.

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A Temporal Switch in the Germinal Center Determines Differential Output of Memory B and Plasma Cells

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