Deepta Bhattacharya

Deepta Bhattacharya

Professor, Immunobiology
Associate Professor, Surgery
Associate Professor, Genetics - GIDP
Associate Professor, Cancer Biology - GIDP
Member of the Graduate Faculty
Associate Professor, BIO5 Institute
Primary Department
Department Affiliations
Contact
(520) 626-8088

Research Interest

Research Interest

Research in the Bhattacharya lab focuses on molecular approaches to direct B cell differentiation to establish immunity to infectious disease, and stem cell differentiation for regenerative medicine. Current projects in the lab include: 1) Understanding the cellular basis of antibody-mediated immunity to variable viruses. After infection or vaccination, B cells that recognize the pathogen proliferate and undergo a massive level of expansion. Upon clearance of the infection a small fraction of the "best" B cells are retained to become memory B cells or long-lived plasma cells. Our recent work has established that memory B cells are excellent at recognizing not only the original pathogen, but also mutant escape variants of the pathogen. In contrast, long-lived plasma cells are highly specific only for the original pathogen. We are studying the transcription factors that regulate the memory B cell vs. long-lived plasma cell fate, and are studying mechanisms to alter this fate to provide effective immunity against mutable viruses such as influenza and Dengue. 2) Identifying molecular regulators of the duration of immunity. Most clinically used vaccines rely on the production of antibodies to confer immunity. The duration of immunity can vary greatly between different vaccines, yet the molecular basis of this remains unknown. Current efforts are focused on the identification of genes that regulate plasma cell lifespan and on the features of the vaccine that confer durable antibody immunity. 3) Engineering human pluripotent stem cells to generate antibody-mediated immunity. A small fraction of patients infected with HIV or dengue virus, or vaccinated against influenza develop remarkable antibodies that neutralize nearly all clinical isolates of these viruses. Yet it is unclear how to induce these types of antibodies in the broader population through standard vaccination. Using novel targeted nuclease technologies, we are engineering human embryonic stem cells to express these antibodies and differentiating them into transplantable long-lived plasma cells. The long-term goal of this project is to provide permanent immunity to recipients of these engineered plasma cells.

Publications

Luckey, C. J., Bhattacharya, D., Goldrath, A. W., Weissman, I. L., Benoist, C., & Mathis, D. (2006). Memory T and memory B cells share a transcriptional program of self-renewal with long-term hematopoietic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 103(9), 3304-9.

The only cells of the hematopoietic system that undergo self-renewal for the lifetime of the organism are long-term hematopoietic stem cells and memory T and B cells. To determine whether there is a shared transcriptional program among these self-renewing populations, we first compared the gene-expression profiles of naïve, effector and memory CD8(+) T cells with those of long-term hematopoietic stem cells, short-term hematopoietic stem cells, and lineage-committed progenitors. Transcripts augmented in memory CD8(+) T cells relative to naïve and effector T cells were selectively enriched in long-term hematopoietic stem cells and were progressively lost in their short-term and lineage-committed counterparts. Furthermore, transcripts selectively decreased in memory CD8(+) T cells were selectively down-regulated in long-term hematopoietic stem cells and progressively increased with differentiation. To confirm that this pattern was a general property of immunologic memory, we turned to independently generated gene expression profiles of memory, naïve, germinal center, and plasma B cells. Once again, memory-enriched and -depleted transcripts were also appropriately augmented and diminished in long-term hematopoietic stem cells, and their expression correlated with progressive loss of self-renewal function. Thus, there appears to be a common signature of both up- and down-regulated transcripts shared between memory T cells, memory B cells, and long-term hematopoietic stem cells. This signature was not consistently enriched in neural or embryonic stem cell populations and, therefore, appears to be restricted to the hematopoeitic system. These observations provide evidence that the shared phenotype of self-renewal in the hematopoietic system is linked at the molecular level.

Sahoo, D., Seita, J., Bhattacharya, D., Inlay, M. A., Weissman, I. L., Plevritis, S. K., & Dill, D. L. (2010). MiDReG: a method of mining developmentally regulated genes using Boolean implications. Proceedings of the National Academy of Sciences of the United States of America, 107(13), 5732-7.

We present a method termed mining developmentally regulated genes (MiDReG) to predict genes whose expression is either activated or repressed as precursor cells differentiate. MiDReG does not require gene expression data from intermediate stages of development. MiDReG is based on the gene expression patterns between the initial and terminal stages of the differentiation pathway, coupled with "if-then" rules (Boolean implications) mined from large-scale microarray databases. MiDReG uses two gene expression-based seed conditions that mark the initial and the terminal stages of a given differentiation pathway and combines the statistically inferred Boolean implications from these seed conditions to identify the relevant genes. The method was validated by applying it to B-cell development. The algorithm predicted 62 genes that are expressed after the KIT+ progenitor cell stage and remain expressed through CD19+ and AICDA+ germinal center B cells. qRT-PCR of 14 of these genes on sorted B-cell progenitors confirmed that the expression of 10 genes is indeed stably established during B-cell differentiation. Review of the published literature of knockout mice revealed that of the predicted genes, 63.4% have defects in B-cell differentiation and function and 22% have a role in the B cell according to other experiments, and the remaining 14.6% are not characterized. Therefore, our method identified novel gene candidates for future examination of their role in B-cell development. These data demonstrate the power of MiDReG in predicting functionally important intermediate genes in a given developmental pathway that is defined by a mutually exclusive gene expression pattern.

Bhattacharya, D. (2015). Basophils take a slice of IRF8 pie. Blood, 125(2), 214-5.

In this issue of Blood, Sasaki and colleagues demonstrate a strict requirement for the transcription factor interferon regulator factor 8 (IRF8) in the development of mouse basophils.

Fathman, J. W., Bhattacharya, D., Inlay, M. A., Seita, J., Karsunky, H., & Weissman, I. L. (2011). Identification of the earliest natural killer cell-committed progenitor in murine bone marrow. Blood, 118(20), 5439-47.

Natural killer (NK) cells develop in the bone marrow and are known to gradually acquire the ability to eliminate infected and malignant cells, yet the cellular stages of NK lineage commitment and maturation are incompletely understood. Using 12-color flow cytometry, we identified a novel NK-committed progenitor (pre-NKP) that is a developmental intermediate between the upstream common lymphoid progenitor and the downstream NKP, previously assumed to represent the first stage of NK lineage commitment. Our analysis also refined the purity of NKPs (rNKP) by 6-fold such that 50% of both pre-NKP and rNKP cells gave rise to NKp46+ NK cells at the single-cell level. On transplantation into unconditioned Rag2-/-Il2rγc-/- recipients, both pre-NKPs and rNKPs generated mature NK cells expressing a repertoire of Ly49 family members that degranulated on stimulation ex vivo. Intrathymic injection of these progenitors, however, yielded no NK cells, suggesting a separate origin of thymic NK cells. Unlike the rNKP, the pre-NKP does not express IL-2Rβ (CD122), yet it is lineage committed toward the NK cell fate, adding support to the theory that IL-15 signaling is not required for NK commitment. Taken together, our data provide a high-resolution in vivo analysis of the earliest steps of NK cell commitment and maturation.

Satpathy, A. T., KC, W., Albring, J. C., Edelson, B. T., Kretzer, N. M., Bhattacharya, D., Murphy, T. L., & Murphy, K. M. (2012). Zbtb46 expression distinguishes classical dendritic cells and their committed progenitors from other immune lineages. The Journal of experimental medicine, 209(6), 1135-52.

Distinguishing dendritic cells (DCs) from other cells of the mononuclear phagocyte system is complicated by the shared expression of cell surface markers such as CD11c. In this study, we identified Zbtb46 (BTBD4) as a transcription factor selectively expressed by classical DCs (cDCs) and their committed progenitors but not by plasmacytoid DCs (pDCs), monocytes, macrophages, or other lymphoid or myeloid lineages. Using homologous recombination, we replaced the first coding exon of Zbtb46 with GFP to inactivate the locus while allowing detection of Zbtb46 expression. GFP expression in Zbtb46(gfp/+) mice recapitulated the cDC-specific expression of the native locus, being restricted to cDC precursors (pre-cDCs) and lymphoid organ- and tissue-resident cDCs. GFP(+) pre-cDCs had restricted developmental potential, generating cDCs but not pDCs, monocytes, or macrophages. Outside the immune system, Zbtb46 was expressed in committed erythroid progenitors and endothelial cell populations. Zbtb46 overexpression in bone marrow progenitor cells inhibited granulocyte potential and promoted cDC development, and although cDCs developed in Zbtb46(gfp/gfp) (Zbtb46 deficient) mice, they maintained expression of granulocyte colony-stimulating factor and leukemia inhibitory factor receptors, which are normally down-regulated in cDCs. Thus, Zbtb46 may help enforce cDC identity by restricting responsiveness to non-DC growth factors and may serve as a useful marker to identify rare cDC progenitors and distinguish between cDCs and other mononuclear phagocyte lineages.