CD8 T cells are critical in controlling infection by intracellular pathogens including viruses and intracellular bacteria. The ability to develop and sustain memory CD8 T cells after infection or immunization constitutes the basis for protective vaccination against infectious disease or in cancer immunotherapy. Since the level of protection against infection depends on the quality and quantity of memory CD8 T cells at the time of pathogen exposure, understanding the mechanisms that govern differentiation and maturation of the memory CD8 T cell pool are critical to our ability to design the most effective vaccines. CD8 T cell-mediated immune responses consist of several distinct stages, including activation of antigen-specific nave CD8 T cells, clonal expansion of effector CD8 T cells, and formation of memory CD8 T cells. A plethora of protein factors including transcriptional regulators have been found to regulate each step of the CD8 T cell response, and high throughput transcriptomic analyses have revealed core gene signatures associated with nave, effector and memory CD8 T cells. In spite of the tremendous progress, several knowledge gaps remains: 1) The heightened protective capacity by memory compared with nave CD8 T cells cannot be solely explained by differences in transcriptomes. What are other molecular features that distinguish memory from nave T cells? 2) Both effector and memory T cells are heterogeneous. What the lineage relationship among these subsets, and what are their defining molecular features? 3) Among the known regulatory factors, what are their target genes and how are they regulated, i.e., how their regulatory functions are coordinated during CD8 T cell responses? We hypothesize that the epigenetic modifications of CD8 T cell genome govern the effector-memory lineage relation and further confer enhanced recall response to memory T cells.
Our specific aim i s to map the dynamic changes of the epigenomes during CD8 T cell responses. We will isolate nave T cells with pre- defined antigen specificity, and activate them using a well-established viral and bacterial infection model to obtain antigen-specific effector and memory T cells. By high throughput sequencing, we will map seven active and repressive histone marks in nave, effector and memory CD8 T cell subsets. By integrative bioinformatics analyses, we will define: 1) Epigenetic code that distinguishes memory from nave CD8 T cells; 2) Lineage relationship among subsets from effector and memory CD8 T cells; 3) Dynamic changes in enhancer organization and activity at each stage of CD8 T cell responses.

Public Health Relevance

CD8 T cells are critical in controlling infection by intracellular pathogens including viruses and intracellular bacteria. This project will investigate the dynamic changes of epigenomes during CD8 T cell activation and further transition into memory T cells. This project will have a major impact on devising new strategies to improve vaccine/adjuvant design, aiming for enhanced T cell immunity against infectious agents and malignant cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI115149-01A1
Application #
8968635
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Kelly, Halonna R
Project Start
2015-05-07
Project End
2017-04-30
Budget Start
2015-05-07
Budget End
2016-04-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Iowa
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52246
Xu, Zhe; Xing, Shaojun; Shan, Qiang et al. (2017) Cutting Edge: ?-Catenin-Interacting Tcf1 Isoforms Are Essential for Thymocyte Survival but Dispensable for Thymic Maturation Transitions. J Immunol 198:3404-3409
Li, Fengyin; He, Bing; Ma, Xiaoke et al. (2017) Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1. Cell Stem Cell 21:359-373.e5
Gullicksrud, Jodi A; Li, Fengyin; Xing, Shaojun et al. (2017) Differential Requirements for Tcf1 Long Isoforms in CD8+ and CD4+ T Cell Responses to Acute Viral Infection. J Immunol 199:911-919
Nish, Simone A; Zens, Kyra D; Kratchmarov, Radomir et al. (2017) CD4+ T cell effector commitment coupled to self-renewal by asymmetric cell divisions. J Exp Med 214:39-47
Shan, Qiang; Zeng, Zhouhao; Xing, Shaojun et al. (2017) The transcription factor Runx3 guards cytotoxic CD8+ effector T cells against deviation towards follicular helper T cell lineage. Nat Immunol 18:931-939
Yu, Shuyang; Li, Fengyin; Xing, Shaojun et al. (2016) Hematopoietic and Leukemic Stem Cells Have Distinct Dependence on Tcf1 and Lef1 Transcription Factors. J Biol Chem 291:11148-60
Yang, Jialong; Lin, Xingguang; Pan, Yun et al. (2016) Critical roles of mTOR Complex 1 and 2 for T follicular helper cell differentiation and germinal center responses. Elife 5:
Lin, Wen-Hsuan W; Nish, Simone A; Yen, Bonnie et al. (2016) CD8+ T Lymphocyte Self-Renewal during Effector Cell Determination. Cell Rep 17:1773-1782
Xing, Shaojun; Li, Fengyin; Zeng, Zhouhao et al. (2016) Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity. Nat Immunol 17:695-703
He, Bing; Xing, Shaojun; Chen, Changya et al. (2016) CD8+ T Cells Utilize Highly Dynamic Enhancer Repertoires and Regulatory Circuitry in Response to Infections. Immunity 45:1341-1354

Showing the most recent 10 out of 12 publications