1. How do immune cells sense, respond and adapt to tissue microenvironment, and how does such local response regulate tissue physiology or pathology?

2. How does metabolism (cellular metabolism and microbial metabolites) modulate immune function?

3. How does the peripheral immune system interact with the central nervous system?

Dr. Wu’ postdoctoral work has made significant contributions to the study of immunology, metabolism and microenvironment: (1) the development of a novel in vivo naive T cell genetic screening system, greatly accelerating in vivo functional study of T cells; (2) the first identification of a gene that is selectively required by pathogenic but dispensable in nonpathogenic Th17 cells, addressing a critical question in the study of Th17 and autoimmunity; and (3) the insight that cellular metabolism can modulate immune cell function in a tissue microenvironment-specific manner, paving new research directions in immunometabolism (Cell, first author and co-corresponding author). In addition, Dr. Wu’s graduate work characterized molecular mechanisms by which three USH I proteins regulate the development of inner ear hair cells and how their mutations lead to deafness (Science, JBC, PNAS). His work has been recognized by a National Multiple Sclerosis Society Postdoctoral Fellowship Award, the NIH/NCI Institutional Postdoctoral Training Grant Award, the Hong Kong Young Scientist Award, and with an invitation to chair a Keystone symposium session etc.

To build upon his postdoctoral findings going forward, Dr. Wu will further investigate the relationship between microbiota, immune system and neuronal system, with the use of mouse models of autoimmune, neurodegenerative and infectious diseases. The questions being asked are 1) how do immune cells orchestrate metabolic adaptation to microenvironments, 2) how do microbial metabolites impact immune function, and 3) how do peripheral immune activities modulate CNS function? Dr. Wu hopes his work can reveal novel mechanisms of immune regulation, and ultimately improve therapeutics for these immune disorders. 

Tang H, Wu L*. MAMPs: a devil tamed becomes an angel. Cell Host & Microbe. 2023. 31(9): 1422-1425

Wu L*, Hollinshead KER, Hao Y, Au C, Kroehling L, Ng C, Lin WY, Li D, Silva HM, Shin J, Lafaille JJ, Possemato R, Pacold ME, Papagiannakopoulos TY, Kimmelman AC, Satija R, Littman DR*. Niche-selective inhibition of pathogenic Th17 cells by targeting metabolic redundancy. Cell. 2020. 182: 641-654. 

Wu L#, Pan L#, Zhang C, Zhang M*. Large protein assemblies formed by multivalent interactions between cadherin23 and harmonin suggest a stable anchorage structure at the tip link of stereocilia. JBC. 2012. 287: 33460-33471 (# equal contribution)

Wu L#, Pan L#, Wei Z, Zhang M*. Structure of MyTH4-FERM domains in myosin VIIa tail bound to cargo. Science. 2011. 331:757-760 (# equal contribution)

Hall JA, Pokrovskii M, Kroehling L, Kim BR, Kim SY, Wu L, Lee JY, Littman DR*. Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element. Immunity. 2022. 55(11): 2027-2043.

Xu H, Wu L, Nguyen H, Mesa KR, Raghavan V, Episkopou V, Littman DR*. Arkadia-SKI/SnoN signaling cascade differentially regulates TGF-β-induced iTreg and Th17 cell differentiation. JEM. 2021. 218 (11): e20210777.

Lee JY, Hall JA, Kroehling L, Wu L, Najar T, Nguyen HH, Lin WY, Yeung ST, Silver HM, Li D, Hine A, Loke P, Hudesman D, Martin JC, Kenigsberg E, Merad M, Khanna KM, Littman DR*. Serum amyloid A proteins induce pathogenic Th17 cells and promote inflammatory disease. Cell, 2020. 180: 79-91.

Hang S, Paik D, Devlin AS, Jamma T, Lu J, Ha S, Nelson BN, Kelly SP, Wu L, Zheng Y, Rastinejad F, Krout MR, Fischbach MA*, Littman DR*, Huh JR*. Bile acid metabolites control Th17 and Treg cell differentiation. Nature, 2019. 576, 143–148.

Ng C, Aichinger M, Nguyen T, Au C, Najar T, Wu L, Mesa KR, Liao W, Quivy JP, Hubert B, Almouzni G, Zuber J, Littman DR*. The histone chaperone CAF-1 cooperates with the DNA methyltransferases to maintain Cd4 silencing in cytotoxic T cells. Genes Dev. 2019. 33: 669-683.

Pan L, Yan J, Wu L, Zhang M*. Assembling stable hair cell tip link complex via multidentate interactions between harmonin and cadherin23. PNAS. 2009. 106: 5575-5580.