Kang Liu, Ph.D.
The main focus of our laboratory is to understand the cellular and molecular events of hematopoiesis of dendritic cells (DCs). DCs are specialized antigen presenting cells and indispensable initiators of immune response. Having a short life, DCs must be constantly replenished through hematopoiesis, a highly organized cellular and molecular process. We recently found that specification to the DC lineage occurs in parallel with specification to the myeloid and lymphoid lineages in hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs). It starts as a lineage bias defined by specific transcriptional programs correlated with the combinatorial dosages of the transcription factors IRF8 and PU.1, which is transmitted to most progeny cells and is reinforced by upregulation of IRF8 expression driven by the hematopoietic cytokine FLT3L during cell division. We therefore propose that combinatorial dosages of a common set of transcription factors in the HSCs and MPPs shape parallel and inheritable programs for distinct hematopoietic lineages, which are then reinforced through recursive interaction with environmental signals during cell division. Our model of DC differentiation is reminiscent of the mechanism of T cell differentiation where Th17 lineage reinforcement and Blimp1 expression are facilitated by recursive interaction between the intrinsic transcription factor IRF4 and the extrinsic signal IL-21 over division, thereby presenting a conserved mechanism used for lineage divergence and maintenance in the immune system.
The exact molecular events underlying such lineage-reinforcing inheritable program are incompletely understood. The capacity to monitor, isolate and manipulate blood progenitors from both mice and humans, at population and single cell level, enables us to study their differentiation potential and gene expression profiles. Using genetic model and patient samples, we investigate extrinsic and intrinsic factors regulating DC hematopoiesis in both mice and humans, in health and disease.
1. Cellular events and epigenetic regulation of DC lineage specification from hematopoietic stem cells and multipotent progenitor cells (HSC-MPPs).
2. Dysregulation of hematopoiesis in patients with primary immunodeficiency and myeloproliferative neoplasm.
3. DC development and function in HIV transmission.
Our long-term goal is to search for novel ways to manipulate DC development and activity, and to apply the findings to vaccine development and treatment of infectious disease and cancer.
- Lee, J., Zhou, Y.J., Ma, W., Zhang, W., Aljoufi, A., Luh, T., Lucero, K., Liang, D., Thomsen, M., Bhagat, G., Shen, Y. and Liu, K. (2017) Lineage specification of human dendritic cells is marked by IRF8 expression in hematopoietic stem cells and multipotent progenitors. Nature Immunology 18: 877-888.
- Collins, A., Rothman, N., Liu, K. and Reiner, S. (2017) Eomesodermin and T-bet mark developmentally distinct human natural killer cells. JCI Insight 2: e90063. Doi:10.1172.
- Liu, K. and Malissen, B. (2016) Advances in methods for studying dendritic cell biology. J. Immunol. Methods 432: 1-3.
- Puhr, S., Lee, J., Zvezdova, E., and Liu, K. (2015) Dendritic Cell Development - History, advances, and open questions. Seminars in Immunology 27: 388-396
- Lee, J., Breton, G., Aljoufi, A., Zhou, Y.J., Puhr, S., Nussenzweig, M.C. and Liu, K. (2015) Clonal analysis of human dendritic cell progenitor using a stromal cell culture. <>Journal of Immunological Methods 425: 21-26.
- Breton, G., Lee, J., Liu, K. and Nussenzweig M.C. (2015) Defining human dendritic cell progenitors by multiparametric flow cytometry. Nature Protocols 10: 1407-1422.
- Lee, J., Breton, G., Oliveira T.Y.K., Zhou, Y.J., Aljoufi, A., Puhr, S., Cameron, M.J., Sekaly, R.P., Nussenzweig, M.C.* and Liu, K.* (2015) Restricted dendritic cell and monocyte progenitors in human cord blood and bone marrow. J. Exp. Med. 212: 385-399. *Co-corresponding
- Breton, G., Lee, J., Zhou, Y.J., Schreiber, J.J., Keler, T., Puhr, S., Anandasabapathy, N., Schlesinger, S., Caskey, M., Liu, K.* and Nussenzweig, M.C.* (2015) Circulating precursors of human CD1c+ and CD141+ dendritic cells. J. Exp. Med. 212: 401-413 *Co-corresponding
- Subramanian, M., Hayes, C.D., Thome, J.J., Thorp, E., Matsushima, G.K., Herz, J., Farber, D.L., Liu, K., Lakshmana, M. and Tabas, I. (2014) An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo. J. Clin. Invest. 124:1296-1308.
- Franklin, R.A., Liao, W., Sarkar, A., Kim, M.V., Bivona, M.R., Liu, K., Pamer, E.G. and Li, M.O. (2014) The cellular and molecular origin of tumor-associated macrophages. Science 344: 921-925.
- Ghosh, H.S., Ceribelli, M., Matos, I., Lazarovici, A., Bussemaker, H.J., Lasorella, A., Hiebert, S.W., Liu, K., Staudt, L.M. and Reizis, B. (2014) ETO family protein Mtg16 regulates the balance of dendritic cell subsets by repressing Id2. J. Exp. Med. 211: 1623-1635.
- Meredith, M.M., Liu, K., Darrasse-Jeze, G., Kamphorst, A.O., Schreiber, H.A., Guermonprez, P., Idoyaga, J., Cheong, C., Yao, K.H., Niec, R.E. and Nussenzweig, M.C. (2012). Expression of the zinc finger transcription factor zDC (Zbtb46, Btbd4) defines the classical dendritic cell lineage. J. Exp. Med. 209: 1153-1165.
- Meredith, M.M., Liu, K., Kamphorst, A.O., Idoyaga, J., Yamane, A., Guermonprez, P., Rihn, S., Yao, K.H., Silva, I.T., Oliveira, T.Y., Skokos, D., Casellas, R. and Nussenzweig, M.C. (2012). Zinc finger transcription factor zDC is a negative regulator required to prevent activation of classical dendritic cells in the steady state. J. Exp. Med. 209: 1583-1593.
- Lewis, K.L., Caton, M.L., Bogunovic, M., Greter, M., Grajkowska, L.T., Ng, D., Klinakis, A., Charo, I.F., Jung, S., Gommerman, J.L., Ivanov, I.I., Liu, K., Merad, M. and Reizis, B. (2011). Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35: 780-791.
- Anandasabapathy, N., Victora, G.D., Meredith, M., Feder, R., Dong, B., Kluger, C., Yao, K., Dustin, M.L., Nussenzweig, M.C., Steinman, R.M. and Liu, K. (2011) Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain. J. Exp. Med. 208: 1695-1705.
- Liu, K. and Nussenzweig, M.C. (2010) Origin and development of dendritic cells. Immunol. Rev. 234: 45-54.
- Ginhoux, F.*, Liu, K.*, Helft, J., Bogunovic, M., Greter, M., Hashimoto, D., Price, J., Yin, N., Bromberg, J., Lira, S.A., Stanley, E.R., Nussenzweig, M. and Merad, M. (2009) The origin and development of nonlymphoid tissue CD103+ DCs. J. Exp. Med. 206: 3115-3130.
- Bogunovic, M., Ginhoux, F., Helft, J., Shang, L., Hashimoto, D., Greter, M., Liu, K., Jakubzick, C., Ingersoll, M.A., Leboeuf, M., Stanley, E.R., Nussenzweig, M., Lira, S.A., Randolph, G.J. and Merad, M. (2009) Origin of the lamina propria dendritic cell network. Immunity 31: 513-525.
- Darrasse-Jeze, G., Deroubaix, S., Mouquet, H., Victoria, G., Eisenreich, T., Yao, K., Rudensky, A., Liu, K. and Nussenzweig, M.C. (2009) Feedback of regulatory T cell homeostasis by dendritic cells in vivo. J. Exp. Med. 206: 1853-1862.
- Liu, K., Victora, G.D.*, Schwickert, T.A.*, Guermonprez, P., Meredith, M.M., Yao, K., Chu, F.F., Randolph, G.J., Rudensky, A.Y. and Nussenzweig, M. (2009) In vivo analysis of dendritic cell development and homeostasis. Science 324: 392-397.
- Waskow, C., Liu, K., Darrasse-Jeze, G., Ginhoux, F., Merad, M., Shengelia, T., Yao, K. and Nussenzweig, M. (2008) Flk2 is required for dendritic cell development in peripheral lymphoid tissues. Nat. Immunol. 9: 676-683.
- Bulloch, K., Miller, M.M., Gal-Toth, J., Milner, T.A., Gottfried, A.B., Waters, E.M., Kaunzner, U.W., Liu, K., Lindquist, R., Nussenzweig, M.C., Steinman, R.M. and McEwen, B.S. (2008) CD11c/EYFP trangsgene illuminates a discrete network of dendritic cells within neonatal, adult and injured mouse brain. J. Comp. Neurol. 508: 687-710.
- Liu, K., Waskow, C., Liu, X., Yao, K., Hoh, J. and Nussenzweig, M. (2007) Origin of dendritic cells in peripheral lymphoid organs of mice. Nat. Immunol. 8: 578-583.
- Dudziak, D., Kamphorst, A.O., Heidkamp, G.F., Buchholz, V.R., Trumpfheller, C., Yamazaki, S., Cheong, C., Liu, K., Lee, H.W., Park, C.G., Steinman R.M. and Nussenzweig, M.C. (2007) Differential antigen processing by dendritic cell subsets in vivo. Science 315: 107-111.
Assistant Professor Kang LiuPhone: