Goldrath, Ananda - University of California, San Diego

研究领域

Immunological memory ensures that, once infected by a particular virus or bacteria, individuals are generally protected from a second encounter with that same pathogen. This ability of lymphocytes to “remember” is the basis for protection following vaccination. Little is known about the signaling pathways and molecular mechanisms that regulate the formation and maintenance of memory T cell numbers and functional capacity. CD8+ T cells are crucial to the control of infection by pathogens that reside in the cytoplasm such as viruses, intracellular bacteria and protozoan parasites. CD8+ T cells recognize pathogen-derived peptides presented by MHC class I molecules, acting as sentinels in the detection of foreign cytoplasmic proteins. Upon encounter with antigen, naive CD8+ T cells proliferate and differentiate to effector T cells, which are armed to eliminate infected cells. Following antigen clearance, the majority of CD8+ effector cells die; however, a subset survive and differentiate further to long-lived memory T cells. The goal of our research is to understand how CD8+ T cell immunological memory is generated and maintained by identifying the transcriptional and signaling events that regulate the survival and differentiation of T cells as they navigate the immune response and become long-lived memory T cells.

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Milner JJ, Toma C, Yu B, Zhang K, Omilusik K, Phan AT, Wang D, Getzler AJ, Nguyen T, Crotty S, Wang W, Pipkin ME*, Goldrath AW*. 2017. Nature. Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumors. 552::253-257. Yu B, Zhang K, Milner JJ, Toma C, Chen R, Scott-Browne JP, Pereira RM, Crotty S, Chang JT, Pipkin ME, Wang W*, Goldrath AW*. 2017. Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation. Nature Immunology. 5:573-582. Shaw LA, Bélanger S, Omilusik KD, Cho S, Scott-Browne JP, Nance JP, Goulding J, Lasorella A, Lu LF, Crotty S*, Goldrath AW*. 2016. Id2 reinforces TH1 differentiation and inhibits E2A to repress TFH differentiation. Nat Immunol. 17(7): 834-43. PMCID: PMC4915968. Omilusik KD, Nadjsombati MS, Shaw LA, Yu B, Milner JJ, Goldrath AW. 2018. Journal of Experimental Medicine. Sustained Id2 regulation of E proteins is required for terminal differentiation of effector CD8+ T cells. 215:773-783. Omilusik KD, Best JA, Yu B, Goossens S, Weidemann A, Nguyen JV, Seuntjens E, Stryjewska A, Zweier C,Roychoudhuri R, Gattinoni L, Bird LM, Higashi Y, Kondoh H, Huylebroeck D, Haigh J, AW Goldrath. Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection. Journal of Experimental Medicine. 2015. 212(12): 2027-39. Chang JT, Wherry EJ, Goldrath AW. Molecular regulation of effector and memory T cell differentiation. Nature Immunology. 2014. 15(12):1104-1115. Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, Johnson RS, Goldrath AW. Hypoxia-Inducible Factors enhance CD8+ T cell effector responses to persistent antigen. Nature Immunology. 2013. Nature Immunology. 14(11):1172-82. Best JA, Blair DA, Knell J, Yang E, Mayya V, Doedens A, Dustin ML, Goldrath AW; The Immunological Genome Project Consortium. Transcriptional insights into the CD8+ T cell response to infection and memory T cell formation. Nature Immunology. 2013 14(4):404-12. Yang CY, Best JA, Knell J, Yang E, Sheridan AD, Jesionek AK, Li HS, Rivera RR, Lind KC, D’Cruz LM, Watowich SS, Murre C, Goldrath AW. The transcriptional regulators Id2 and Id3 control formation of distinct CD8+ memory T cell subsets. Nature Immunology. 2011 12(12):1221-29. D'Cruz LM, Knell J, Fujimoto JK, Goldrath AW. An essential role for the transcription factor HEB in thymocyte survival, Tcra rearrangement and the development of natural killer T cells. Nat Immunol. 2010 Mar;11(3):240-9. Cheung KP, Yang E, Goldrath AW. Memory-like CD8+ T cells generated during homeostatic proliferation defer to antigen-experienced memory cells. J Immunol. 2009 Sep 1;183(5):3364-72. Cannarile MA, Lind NA, Rivera R, Sheridan AD, Camfield KA, Wu BB, Cheung KP, Ding Z, Goldrath AW. Transcriptional regulator Id2 mediates CD8+ T cell immunity. Nat Immunol. 2006 Dec;7(12):1317-25.