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Chance J. Luckey, MD, PhD
Associate Pathologist, Brigham and Women's Hospital
Assistant Professor of Pathology, Harvard Medical School

Brigham and Women's Hospital
Department of Pathology
75 Francis Street
Boston, MA 02115

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Research Narrative:

    Effective vaccination depends the generation of immunological memory. The primary focus of my research is to identify the molecular signals which, in response to either viral or bacterial infection, drive memory cell formation and subsequent self-renewal. Memory T and B cells are the only non-stem cells capable of self-renewal in the hematopoietic system. My lab works on the central hypothesis that memory T cells rely on pathways that are homologous to the core self-renewal pathways present in stem cells. Our initial transcriptional profiling of memory CD8+ cells relative to other T cell populations provided a detailed view of the genes whose transcription is enriched in memory cells (refs 4 and 6 below). Interestingly, these transcripts are also enriched in hematopoietic stem cells, suggesting memory T cells and hematopoietic stem cells share a common transcriptional profile (ref 5).

     To better understand how external signaling pathways can be translated into a core transcriptional program driving self-renewal and cell fate maintenance, we first studied embryonic stem cells (ESC). ESC are remarkable cells because in response to specific cues, they can in principle be coaxed into becoming nearly any cell type in the body. Thus there is a growing enthusiasm that embryonic stem cells will become the starting point for a wide range of cellular therapies. Before these remarkable cells can be used in clinical applications, we must first understand how to reproducibly turn them into a specific type of cell: i.e. a hematopoietic stem cell, a pancreatic islet cell, or a particular type of neuron. Such differentiated cells can then be used to replace their diseased or destroyed counterparts in patients.

     In our ESC work, we have collaborated closely with the mass spectrometry lab of Dr. Jarrod Marto at the Dana Farber Cancer Institute. Together, our labs have employed advanced, quantitative phospho- proteomic analyses (ref 7) to identify protein pathways that are activated early in ESC differentiation and downstream of the key self-renewal cytokine, Leukemia Inhibitory Factor (LIF). In the course of these experiments, we made the unexpected observation that many phospho-protein substrates downstream of LIF were proteolytically cleaved by caspase 9 (Casp9), and that this cleavage correlated with subsequent ESC differentiation. This is in keeping with recent reports that caspase activation can in some cases drive cell fate changes instead of apoptosis. Collectively our data and observations support the intriguing hypothesis that activation of Casp9 is one of the earliest molecular events in ESC differentiation, and furthermore that substrates, perhaps targeted as a result of phosphorylation, are cleaved into functional fragments that act at the epigenetic and transcriptional level to regulate ESC differentiation.  We are currently testing whether in addition to ESC differentiation, these pathways might also be involved in reprogramming of differentiated human fibroblasts back into induced pluripotent stem cells (iPS). We believe that this paradigm will serve as a general model for developmental systems whereby tightly regulated, phosphorylation-directed caspase cleavage of proteins generates functionally discrete protein domains that drive cell fate transitions.

     Given my lab’s ultimate interest in studying self-renewal in T cells as well as stem cells, we are now asking whether the protein pathways and signaling events observed in stem cells are conserved in CD8+ T cells. We have started to use our phospho-proteomics techniques to investigate T cell signaling ex vivo. Furthermore, we are beginning the in vivo study of CD8+ T cell responses in mice that lack either LIF, the LIF-Receptor, or specific caspase function. Finally, we are in the process of generating a new mouse strain which expresses a conditional disruption of a POU domain transcription factor that is a close homologue of OCT4, and is uniquely expressed in memory T cells, memory B cells, and hematopoietic stem cells. This conditional knock-out strain will be used to assess the functional role of this transcription factor in each of these three cell populations. As in ESC, we believe LIF (and likely caspase) signaling ultimately converges on a group of coordinately regulated transcription factors, one of which is a POU domain factor. Our cross-cultural studies in stem cells and memory T cells uniquely position my lab to apply the recent advances in stem cells to elucidate how memory CD8+ T cells self-renew. Ultimately, my research goal is to understand how immune memory is established, with the hope that our findings will help further the design of more rational and effective vaccine strategies.

Selected Publications:
1.    Luckey CJ, King GM, Marto JA, Vanketeswaran S, Maier BF, Crotzer VL, Colella TA, Shabanowitz J, Hunt DF, Engelhard VH. Proteasomes can either generate or destroy MHC Class I epitopes: evidence for non-proteasomal epitope generation in the cytosol.  J Immunol 1998; 161(1):112-21.
2.    Luckey CJ, Marto JA, Partridge M, Hall E, White FM, Lippolis JD, Shabanowitz J, Hunt DF, Engelhard VH. Differences in the Expression of Human Class I MHC Alleles and Their Associated Peptides in the Presence of Proteasome Inhibitors. J Immunol 2001; 167(3):1212-21.
3.    Zarling AL*, Luckey CJ*, Marto JA, White FM, Brame CJ, Evans AM, Lehner PJ, Cresswell P, Shabanowitz J, Hunt DF, and Engelhard VH. Tapasin is a facilitator, not an editor, of Class I MHC peptide binding.  J Immunol 2003;171(10):5287-95. (*authors contributed equally to this work.)
4.    Goldrath AW, Luckey CJ, Park R, Benoist C, and Mathis D. The molecular program induced in T cells undergoing homeostatic proliferation. P Natl Acad Sci USA 2004; 101(48): 16885-90.
5.    Luckey CJ*, Bhattacharya D*, Goldrath AW*, Weissman IL, Benoist C, and Mathis D. Memory T and memory B cells share a transcriptional program of self-renewal with Long-term Hematopoietic Stem Cells. P Natl Acad Sci USA 2006; 103(9):3304-9. (*authors contributed equally to this work.)
6.    Hyatt G, Melamed R, Park R, Seguritan R, Laplace C, Poirot L, Zucchelli S, Obst R, Matos M, Venanzi E, Goldrath A, Nguyen L, Luckey J, Yamagata T, Herman A, Jacobs J, Mathis D  and Benoist C. Gene expression microarrays: glimpses of the immunological genome. Nat Immunol 2006; 7, 686 – 691.
7.    Scott B. Ficarro, Yi Zhang, Yu Lu, Ahmadali R. Moghimi, Manor Askenazi, Elzbieta Hyatt, Eric D. Smith, Leah Boyer, Thorsten Schlaeger, C. John Luckey, Jarrod A. Marto. Improved Electrospray Ionization Efficiency Compensates for Diminished Chromatographic Resolution and Enables Proteomics Analysis of Tyrosine Signaling in Embryonic Stem Cells. Analytical Chemistry. Manuscript Accepted.


Lab Members:
Marlene Carrasco-Alfonso, MD, PhD, Postdoctoral Research Fellow
Yu Lu, PhD, Postdoctoral Research Fellow