Dana Farber Cancer Institute
Pediatric Oncology, Dana 640D
44 Binney St.
Boston, MA 02115
Lab Members: 4 Post-doctoral Fellows, 2 Graduate Students, 2 Technicians
Visit my lab page here.
Our laboratory studies the mechanisms that regulate T cell function in humans. Our goal is to understand how functional memory T cells are formed, and why protective T cell immunity fails to develop against chronic viral infection and cancer. We use a range of experimental approaches that includes cellular immunology, functional genomics and chemical biology.
Questions that we are studying include:
What are the mechanisms that impair the function of T cells responding to cancer and chronic viral disease?
One of the central challenges in human immunology is understanding why T cells that are capable of recognizing chronic viral pathogens and tumor antigens do not function effectively and fail to protect the host from disease. We have developed the experimental and analytic tools to study the complex patterns of gene expression in tiny populations of T cells specific for antigens from viruses like HIV and HCV, and from tumors like melanoma. These studies have allowed, for the first time, comprehensive analysis of the gene expression programs in T cells responding to viral pathogens, and have begun to identify the molecular differences between defective immune responses and those that effectively control viral infections.
We have developed the tools to apply functional genomic approaches to identify novel regulators of T cell function. For instance, we have show that the transcription factor BATF plays a crucial role in impairing the function of HIV-specific T cells. BATF becomes upregulated following signaling through an inhibitory receptor, PD-1, resulting in increased BATF levels that inhibit T cell function. This suggests that BATF and the pathways that control its activity represent a novel therapeutic target to improve T cell immunity in chronic viral infections like HIV.
Can the function of T cells in cancer and chronic viral infection be resuscitated?
We are actively involved in the identification and development of small molecules that could be useful for the treatment of T cell dysfunction in diseases like HIV and cancer. We are studying compounds that can interfere with negative regulatory signals that are involved in suppressing the T cell response to chronic viral infection. In addition we are combining chemical and genetic screening approaches to identify compounds that can make T cell responses to vaccines more effective.
1. Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, Eichbaum Q, Julg B, Jesneck JL, Brosnahan K, Imam S, Russell K, Toth I, Piechocka-Trocha A, Dolfi D, Angelosanto J, Crawford A, Shin H, Kwon DS, Zupkosky J, Francisco L, Freeman GJ, Wherry EJ, Kaufmann DE, Walker BD, Ebert B, Haining WN. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med 2010, 16:1147-1151.(PMID: 20890291)
2. Haining WN, Wherry EJ. Integrating genomic signatures for immunologic discovery. Immunity 2010, 32:152-161.(PMID: 20189480)
3. Haining WN, Ebert BL, Subrmanian A, Wherry EJ, Eichbaum Q, Evans JW, Mak R, Rivoli S, Pretz J, Angelosanto J, Smutko JS, Walker BD, Kaech SM, Ahmed R, Nadler LM, Golub TR. Identification of an evolutionarily conserved transcriptional signature of CD8 memory differentiation that is shared by T and B cells. J Immunol 2008, 181:1859-1868.(PMID: 18641323)
4. Haining WN, Angelosanto J, Brosnahan K, Ross K, Hahn C, Russell K, Drury L, Norton S, Nadler L, Stegmaier K. High-throughput gene expression profiling of memory differentiation in primary human T cells. BMC Immunol 2008, 9:44.(PMID: 18673556)
Last Update: 12/13/2012