Research/Clinical Interest
Transcriptional regulation of adaptive immunity (Tfh cell differentiation, GC responses, CD8+ T cell quiescence/activation, T cell responses, immune memory, vaccines)
T cell differentiation, humoral responses, memory, infection, vaccines
Our laboratory utilizes a broad variety of techniques including cellular immunology, molecular biology, biochemistry, gene-targeting (knockout and knockin), functional genomics, and in vivo animal models to address the questions that we are interested in.
I. Tfh cell differentiation and humoral immunity
The humoral immune response is one of the two effector arms of the immune system. Studies have shown that CD4+ T follicular helper (Tfh) cells are essential for long-lived, high affinity antibody responses. Yet the complex regulation that determines the initial development of Tfh cells, their developmental progression in germinal centers (GC), and their fates after an immune response dissolves, is still not fully understood. In this research direction, our long-term goals are to identify novel pathways underlying the differentiation of Tfh cells in humoral responses, and design new strategies to manipulate humoral responses for treatment of infectious diseases and autoimmune disorders.
Recently, we find that Foxp1 is a rate-limiting and essential negative regulator of Tfh cell differentiation, drastically affecting GC and antibody responses (Nat. Immunol. 2014).
Rotation/research projects:
1. To elucidate the detailed molecular mechanisms by which the Foxp1 pathway/network regulates the differentiation and function of Tfh cells.
2. To further dissect how the Foxp1 pathway in T cells may regulate the key steps of mature B cell differentiation in GC responses.
3. To determine how the Foxp1 pathway in T cells may regulate other important components including innate immunity in a GC response.
4. To determine how we may manipulate the Foxp1 pathway to boost humoral responses and vaccine efficacy by combining with different types of vaccinations.
II. Negative regulatory pathways in controlling T cell quiescence and responses
Much of our understanding of molecular mechanisms regulating immune responses is centered on pathways and processes that promote cell activation, division and differentiation. Recently we have demonstrated that cell-intrinsic signaling pathways are required to maintain mature T cells in a quiescent state (Nat. Immunol. 2011). If these pathways are disrupted, resting T cells become aberrantly activated even in the absence of antigen challenge. In this research direction, our long-term goals are to identify regulatory genes and pathways that actively restrain T cell activation, and define the roles of such negative regulatory pathways in controlling T cell quiescence, effector responses, memory maintenance, and tumor immunology.
Rotation/research projects:
1. To elucidate the molecular mechanisms underlying T cell quiescence.
2. To determine how quiescence pathways regulate effector T cell responses and T cell memory by using various infectious disease models.
3. To develop new adoptive T-cell immunotherapies in treatment of cancer.
Selected Publications:
Wang, H., Geng J., Wen, X., Bi, E., Kossenkov, A. V., Wolf, A. I., Tas, J., Choi, Y.S., Takata, H., Day, T. J., Chang, L-Y., Sprout, S. L., Becker, E. K., Willen, J., Li, T., Wang, Xin., Xiao C., Jiang, P., Crotty, S., Victora, G.D., Showe, L. C., Tucker, H. O., Erikson, J. and Hu, H. (2014) The transcription factor Foxp1 is a critical negative regulator of T follicular helper cell differentiation. Nature Immunology. (in press)
Feng, X., Wang, H., Takada, H., Day, T., Willen, J. and Hu, H. (2011) Transcription factor Foxp1 exerts essential cell-intrinsic regulation of the quiescence of naive T cells. Nature Immunology. 12, 544-550 (see News and Views in Nat. Immunol. 12, 522-524; featured as Article of the month).
Feng, X., Ippolito, G. C., Tian, L., Karla, W., Oh, S., Sambandam, A., Willen, J., Bunte, R. M., Maika, S. D., Harriss, J.V., Caton, A. J., Bhandoola, A., Tucker, P. W., and Hu, H. (2010) Foxp1 is an essential transcriptional regulator for the generation of quiescent naïve T cells during thymocyte development. Blood. 115, 510-518.
Hu, H., Djuretic, I., Sundrud, M.S. and Rao, A. (2007) Transcriptional partners in regulatory T cells: Foxp3, Runx and NFAT. Trends. Immunol. 28, 329-332.
Hu, H., Wang, B., Borde, M., Maika, S., Nardone, J., Allred, L., Tucker, P.W. and Rao, A (2006) Foxp1 is an essential transcriptional regulator of B cell development. Nature Immunology. 7, 819-826 (see News and Views in Nat. Immunol. 7, 793-794).
Hu, H., Huston, G., Duso, D., Lepak, N., Roman, E. and Swain, S.L. (2001) CD4 T cell effectors can become memory cells with high efficiency and without division. Nature Immunology. 2, 705-710.
Swain, S. L., Hu, H. and Huston, G. (1999) Class II independent generation of CD4 memory T cells from effectors. Science. 286, 1381-1383.
