During infection the adaptive immune response has two primary goals, a short-term goal to eradicate the present infection and a long-term goal to establish immunological memory and protect against re- infection. These two goals are fulfilled by generating a heterogeneous pool of activated T and B cells that contain both short-term effector cells and memory cell precursors that persist long-term to seed a + pool of memory cells and provide exceptional protection agianst reinfection. Because cytotoxic CD8 T lymphocyte (CTL) responses are critical for clearing many types of intracellular infections and tumors, the development of many vaccines (e.g., HIV and plasmodium) are aimed at generating protective memory CD8 T cells. The question of how different types of memory T cells form during infection and vaccination and what genetic pathways and epigenetic changes control this process remains paramount. This past decade represents the dawn of a molecular understanding of memory CD8 T cell development, which largely through the use of well-characterized infection models in mice has discovered critical transcription factors and cytokine signaling pathways involved in this process. This work has delivered unprecedented insight into the genetic pathways that control memory T cell differentiation, but we are still in a discovery phase as only a handful of factors (cytokines and transcription factors (TFs)) have been identified that modulate effector and memory CD8 T cell differentiation in vivo during infection. Moreover, it is unclear how such factors cooperate or combat one another activities or to regulate the epigenetic states that specify effector and memory T cell fates. Elucidating these genetic and epigenetic networks is necessary to understand how the effector and memory T cell differentiation is controlled. It is likely that we will only really start to understand how T cell fates are specified and how the inherent heterogeneity and plasticity observed in T cells is controlled through studying the epigenome of T cells. Thus, the overarching goals of this MERIT extension are to elucidate genetic and epigenetic control of effector and memory CD8 T cell differentiation, plasticity and heterogeneity. This proposal will not only provide new insight on novel genetic regulators of effector and memory T cell development, but it will also reveal how effector T cell plasticity or commitment to terminal fates is regulated at the genomic level.

Public Health Relevance

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Kelly, Halonna R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Salk Institute for Biological Studies
La Jolla
United States
Zip Code
Guan, Tianxia; Dominguez, Claudia X; Amezquita, Robert A et al. (2018) ZEB1, ZEB2, and the miR-200 family form a counterregulatory network to regulate CD8+ T cell fates. J Exp Med 215:1153-1168
Herndler-Brandstetter, Dietmar; Ishigame, Harumichi; Shinnakasu, Ryo et al. (2018) KLRG1+ Effector CD8+ T Cells Lose KLRG1, Differentiate into All Memory T Cell Lineages, and Convey Enhanced Protective Immunity. Immunity 48:716-729.e8
Roberts, Natalie A; Adams, Brian D; McCarthy, Nicholas I et al. (2017) Prdm1 Regulates Thymic Epithelial Function To Prevent Autoimmunity. J Immunol 199:1250-1260
Buck, Michael D; Sowell, Ryan T; Kaech, Susan M et al. (2017) Metabolic Instruction of Immunity. Cell 169:570-586
Gray, Simon M; Amezquita, Robert A; Guan, Tianxia et al. (2017) Polycomb Repressive Complex 2-Mediated Chromatin Repression Guides Effector CD8+ T Cell Terminal Differentiation and Loss of Multipotency. Immunity 46:596-608
Laidlaw, Brian J; Craft, Joseph E; Kaech, Susan M (2016) The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nat Rev Immunol 16:102-11
Laidlaw, Brian J; Cui, Weiguo; Amezquita, Robert A et al. (2015) Production of IL-10 by CD4(+) regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells. Nat Immunol 16:871-9
Ho, Ping-Chih; Bihuniak, Jessica Dauz; Macintyre, Andrew N et al. (2015) Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell 162:1217-28
Cui, Guoliang; Staron, Matthew M; Gray, Simon M et al. (2015) IL-7-Induced Glycerol Transport and TAG Synthesis Promotes Memory CD8+ T Cell Longevity. Cell 161:750-61
Dominguez, Claudia X; Amezquita, Robert A; Guan, Tianxia et al. (2015) The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection. J Exp Med 212:2041-56

Showing the most recent 10 out of 20 publications