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Epigenomics of Human CD8 T cell Differentiation and Aging

ABSTRACT:

The efficacy of the adaptive immune response declines dramatically with age, but the cell-intrinsic mechanisms driving the changes characteristic of immune aging in humans remain poorly understood. One hallmark of immune aging is the loss of self-renewing naive cells and the accumulation of differentiated but dysfunctional cells within the CD8 T cell compartment. Using ATAC-seq, we first inferred the transcription factor binding activities that maintain the naive and central and effector memory CD8 T cell states in young adults. Integrating our results with RNA-seq, we determined that BATF, ETS1, Eomes, and Sp1 govern transcription networks associated with specific CD8 T cell subset properties, including activation and proliferative potential. Extending our analysis to aged humans, we found that the differences between memory and naive CD8 T cells were largely preserved across age, but that naive and central memory cells from older individuals exhibited a shift toward a more differentiated pattern of chromatin openness. Additionally, aged naive cells displayed a loss in chromatin openness at gene promoters, a phenomenon that appears to be due largely to a loss in binding by NRF1, leading to a marked drop-off in the ability of the naive cell to initiate transcription of mitochondrial genes. Our findings identify BATF- and NRF1-driven gene regulation as targets for delaying CD8 T cell aging and restoring T cell function.

PROVIDER: phs001187 | dbGaP |

SECONDARY ACCESSION(S): PRJNA338721PRJNA338720

REPOSITORIES: dbGaP

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Project description:This lab investigates how protein-carbohydrate interactions affect cell fate in the immune system. The specific focus is on the mechanism of galectin-1 mediated death of T lymphocytes, and the role of galectin-1 in immune development, lymphocyte homeostasis, response to pathogens, autoimmunity and tumor cell evasion of the immune response. T cell memory, the ability of T cells to respond to recall antigens rapidly and effectively, is a critical component of the adaptive immune response and the essential target of vaccine development. After naive T cells are exposed to a new antigen (or pathogen), expansion of antigen-specific T cells creates an effector population; the majority of effector T cells die once the antigen or pathogen is cleared. A small subset of T cells remains after antigen is cleared, the memory T cells. These memory cells can respond more rapidly than naive cells to recall antigen, and are also capable of homeostatic self-renewal. During the development of T cell memory, there are dramatic changes in gene transcription, protein expression and post-translational modification of proteins, compared to naive and effector T cells. Our labs have described some of these changes at the phenotypic level, and have found important distinctions in the glycotypes of naive, effector and memory T cells. However, there has not been a systematic examination of differential glycosyltransferase expression among these T cell populations. Gene expression during the development of T-cell memory: After naive T cells are exposed to a new antigen (or pathogen), expansion of antigen-specific T cells creates an effector T cell population, the majority of which dies once antigen is cleared. A small subset, the memory T cells, remains after antigen is cleared. Using the LCMV system in P14 TCR transgenic mice specific for the DbGP33-41 epitope of LCMV, RNA (triplicate samples) was isolated from FACS-sorted virus-specific CD8+ T-cell populations during a time course following viral infection. The time points are day 0, day 8 (the peak of T-cell expansion following viral infection), day 15 (during the contraction or apoptotic phase), day 22 (during the transitional phase), and day 40 or later (the stable memory phase). The RNA samples were analyzed by Glyco-gene Chip analysis.

Project description:During a T cell response, naÃ¯ve CD8 T cells differentiate into effector cells. Subsequently, a subset of effector cells termed memory precursor effector cells (MPECs) further differentiates into functionally mature memory CD8 T cells. The transcriptional network underlying this carefully scripted process is not well understood. Here, we report that the transcription factor FoxO1 plays an integral role in facilitating effector to memory transition and functional maturation of memory CD4 and CD8 T cells. We find that FoxO1 is not required for differentiation of effector cells, but in the absence of FoxO1, memory CD8 T cells displayed features of scenescence and progressive attrition in polyfunctionality, which in turn led to impared recall responses and poor protective immunity. These data suggest that FoxO1 is essential for active maintenance of functional CD8 T cell memory and protective immunity. Under competing conditions in bone marrow Single-cell suspensions from splenocytes of eight samples WT (control) and FoxO1-/- (experimental) LCMV-immune mice were prepared using standard procedures. CD8 T cells were then isoloated using Thy1.2 (CD90.2) (30-H12) microbeads (Miltenyi Biotec). Cells were then stained with anti-CD8, anti-CD44 and Db/NP396 MHC class I tetramer. Activated (CD8+CD44hi), naive (CD8+CD44lo), and virus-specific CD8 T cells were sorted using FACSAria II instrument (BD Biosciences). The purity of the cells was >95%. Total RNA was extracted from the sorted cells by Trizol Reagent. RNA samples were reverse transcribed and Cy3-labeled cDNAs were hyrbidized to Agilent whole Mouse Genome Oligo Microarrays. Fluorscence signals were detected using Agilent's Microarray Scanner system, data was analyzed using the Rosetta Resolver gene expression data analysis system and genes with a fold change < and p-values <0.01 were identified. Microarray data discussed in the paper is focused on virus-specific memory CD8 T cells from samples WT_Tet_2 vs KO_Tet_2.

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Epigenomics of Human CD8 T cell Differentiation and Aging

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