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* Department of Pediatric Oncology and
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115;
Division of Hematology/Oncology, Children’s Hospital, Boston, MA 02115;
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142;
¶ Division of Hematology, Brigham and Women’s Hospital, Boston, MA 02115;
|| Immunology Program, Wistar Institute, Philadelphia, PA 19104;
# Nugen Technologies, San Carlos, CA 94070;
** Department of Immunobiology, Yale University, New Haven, CT 06520;
Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322; and
* Partners AIDS Research Center, Massachusetts General Hospital and Division of AIDS, Boston, MA 02114
After Ag encounter, naive lymphocytes differentiate into populations of memory cells that share a common set of functions including faster response to Ag re-exposure and the ability to self-renew. However, memory lymphocytes in different lymphocyte lineages are functionally and phenotypically diverse. It is not known whether discrete populations of T and B cells use similar transcriptional programs during differentiation into the memory state. We used cross-species genomic analysis to examine the pattern of genes up-regulated during the differentiation of naive lymphocytes into memory cells in multiple populations of human CD4, CD8, and B cell lymphocytes as well as two mouse models of memory development. We identified and validated a signature of genes that was up-regulated in memory cells compared with naive cells in both human and mouse CD8 memory differentiation, suggesting marked evolutionary conservation of this transcriptional program. Surprisingly, this conserved CD8 differentiation signature was also up-regulated during memory differentiation in CD4 and B cell lineages. To validate the biologic significance of this signature, we showed that alterations in this signature of genes could distinguish between functional and exhausted CD8 T cells from a mouse model of chronic viral infection. Finally, we generated genome-wide microarray data from tetramer-sorted human T cells and showed profound differences in this differentiation signature between T cells specific for HIV and those specific for influenza. Thus, our data suggest that in addition to lineage-specific differentiation programs, T and B lymphocytes use a common transcriptional program during memory development that is disrupted in chronic viral infection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants K08 HL72750, U19 CA100265, R01HL82945, and the Howard Hughes Medical Institute.
2 W.N.H. and B.L.E. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Todd Golub, Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142l. E-mail address: golub{at}broad.mit.edu
4 Abbreviations used in this paper: GSEA, gene set enrichment analysis; ES, enrichment score; LCMV, lymphocytic choriomeningitis.
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  D. E. Kaufmann and B. D. Walker PD-1 and CTLA-4 Inhibitory Cosignaling Pathways in HIV Infection and the Potential for Therapeutic Intervention J. Immunol., May 15, 2009; 182(10): 5891 - 5897. [Abstract] [Full Text] [PDF]
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