Adaptive immunity to pathogens hinges upon separate processes for short- and long-term increases in the activity of antigen-specific B and T lymphocytes. Short-term multiplication and differentiation of plasma cells and cytotoxic T cells is critical for resolving an existing infection, but the strength of the immediate response needs to be balanced with the processes that establish long-term immunity such as affinity maturation, formation of memory B and T cells, and differentiation of long-lived bone marrow plasma cells. Much remains unknown about the genetic and systems-level decision-making that guides these short- and long-term processes. Without that understanding there are major gaps in strategies to establish and improve vaccines against many NIH Priority Pathogens, and to interpret patterns of human genetic, cellular, and serological variation to predict the efficacy and longevity of immunity in clinical settings and in the field. This project, in synergy with the Cores and other projects of this U19 program, will expand the community resource of mouse mutations and datasets that experimentally connect discrete genes with the cells and systems governing short- and long-term adaptive immunity. These resources and datasets will be distributed to the community via repositories and websites to enable researchers to test their own hypotheses about adaptive immunity. In addition, the project will focus on a subset of novel gene mutations affecting memory versus effector decisions or antibody affinity maturation in the context of immunity to NIH Priority Pathogens, and determine the cellular and molecular systems controlled by these genes.
Immunity to viruses and bacteria, especially those representing potential bio-terrorism agents and emerging diseases, depends upon thousands of mostly unexplored genes that come together in sophisticated control systems coordinating the production of antibodies and T cells of the immune system. This project will define these genes and systems, and thereby open the way for new technologies to promote immunity against these agents.
|Bendall, Sean C; Davis, Kara L; Amir, El-Ad David et al. (2014) Single-cell trajectory detection uncovers progression and regulatory coordination in human B cell development. Cell 157:714-25|
|Zak, Daniel E; Tam, Vincent C; Aderem, Alan (2014) Systems-level analysis of innate immunity. Annu Rev Immunol 32:547-77|
|Gaudillière, Brice; Fragiadakis, Gabriela K; Bruggner, Robert V et al. (2014) Clinical recovery from surgery correlates with single-cell immune signatures. Sci Transl Med 6:255ra131|
|Knijnenburg, Theo A; Ramsey, Stephen A; Berman, Benjamin P et al. (2014) Multiscale representation of genomic signals. Nat Methods 11:689-94|
|Gold, Elizabeth S; Diercks, Alan H; Podolsky, Irina et al. (2014) 25-Hydroxycholesterol acts as an amplifier of inflammatory signaling. Proc Natl Acad Sci U S A 111:10666-71|
|Yang, Yong; Kulka, Kathleen; Montelaro, Ronald C et al. (2014) A hydrolase of trehalose dimycolate induces nutrient influx and stress sensitivity to balance intracellular growth of Mycobacterium tuberculosis. Cell Host Microbe 15:153-63|
|Altin, John A; Daley, Stephen R; Howitt, Jason et al. (2014) Ndfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4+ T cells. Proc Natl Acad Sci U S A 111:2067-74|
|Zeng, Ming; Hu, Zeping; Shi, Xiaolei et al. (2014) MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses. Science 346:1486-92|
|Angelo, Michael; Bendall, Sean C; Finck, Rachel et al. (2014) Multiplexed ion beam imaging of human breast tumors. Nat Med 20:436-42|
|Wang, James Q; Jeelall, Yogesh S; Beutler, Bruce et al. (2014) Consequences of the recurrent MYD88(L265P) somatic mutation for B cell tolerance. J Exp Med 211:413-26|
Showing the most recent 10 out of 23 publications