Littman Laboratory: T Cell Development and Retroviral Pathogenesis

Maria Ciofani

Maria Ciofani
Leukemia & Lymphoma Society Fellow
Ph.D. University of Toronto
maria.ciofani@med.nyu.edu

During an immune response, naïve CD4 T cells may differentiate into a variety of T helper (Th) cell effectors—Th1, Th2, or Th17—dependent largely on differential cytokine signals provided by antigen presenting cells. Downstream of such signals, specific transcription factors orchestrate the differentiation programs that specify distinct effector functions and cellular identities. IL-17-producing T lymphocytes have recently been shown to comprise a discrete lineage of proinflammatory helper T cells, termed Th17 cells, that are major contributors to the development of autoimmune disease. Our group has identified RORγt as a key transcription factor regulating Th17 development, being both necessary and sufficient for the generation of IL-17-producing cells. The major aim of my work is to delineate the RORγt-dependent transcriptional network that underlies Th17 specification. This will be accomplished by employing Chromatin immunoprecipitation followed by high throughput sequencing (ChIP-Seq) to compile a genome-wide map of direct RORγt binding sites. This strategy will be coupled with gene expression profiling of RORγt-deficient T cells activated under Th17-polarizing conditions in order to distinguish activating versus repressive RORγt functions.

Publications

Michie AM, Chan AC, Ciofani M, Carleton M, Lefebvre JM, He Y, Allman DM, Wiest DL, Zúñiga-Pflücker JC, and Izon DJ. (2007). Constitutive Notch signaling promotes CD4 CD8 thymocyte differentiation in the absence of the pre-TCR complex, by mimicking pre-TCR signals. Int. Immunol. 12:1421-1430.

Koltsova EK, Ciofani M, Benezra R, Miyazaki T, Clipstone N, Zúñiga-Pflücker JC, and Wiest DL. (2007). Early growth response 1 and NFATc1 act in concert to promote thymocyte development beyond the -selection checkpoint. J Immunol. 179:4694-4703.

Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, Caparros E, Buteau J, Brown K, Perkins SL, Bhagat G, Basso G, Accili D, Parsons R, Zúñiga-Pflücker JC, Dominguez M, and Ferrando AA. (2007). Mutational loss of PTEN induces an oncogene addiction switch and promotes resistance to NOTCH1 inhibition in T-cell leukemia. Nat Medicine 13:1203-1210.

Ciofani M, and Zuniga-Pflucker JC. (2007). The Thymus as an Inductive Site for T Lymphopoiesis Annu Rev Cell Dev Biol. Vol. 23, 23:463-493.

Aublin A, Ciofani M, Willkomm N, Szymczak-Workman AL, Takahashi T, Sandjeu Y, Vignali DAA, Michielin O, Zuniga-Pflucker JC. (2006). A natural structural variant of the moust TCRb-chain displays intrinsic receptor function and antigen specificity J Immunol. 177:8587-8594.

Ciofani M, Knowles GC, Wiest DL, von Boehmer H, and Zuniga-Pflucker JC. (2006). Stage-specific and differential Notch dependency at the alpha/beta and gamma/delta T lineage bifurcation Immunity 25, 105-116.

Zuniga-Pflucker JC, and Ciofani M. (2006). Pre-T cell receptor's clashing signals: "Should I Stay or Should I Go" Immunity 24:669-670.

Ciofani M, and Zuniga-Pflucker JC. (2006). A survival guide to early T cell development. Immunol Res. 32:117-132.

Ciofani M, Zuniga-Pflucker JC. (2005). Notch promotes survival of pre-T cells at the B-selection checkpoint by regulating cellular metabolism. Nat Immunol.6:881-888.

Mandal M, Borowski C, Palomero T, Ferrando AA, Oberdoerffer P, Meng R, Ruiz-Vela A, Ciofani M, Zuniga-Pflucker JC, Screpanti I, Look AT, Korsmeyer SJ, Rajewsky K, von Boehmer H, and Aifantis I. (2005). The BCL2A1 gene as a pre-T cell receptor-induced regulator of thymocyte survival J Exp Med. 201:603-614.

Schmitt TM, Ciofani M, Petrie HT, and Zuniga-Pflucker JC. (2004). Maintenance of T cell specification and differentiation require recurrent notch receptor-ligand interactions. J Exp Med. 200:469-479.

Ciofani M, Schmitt TM, Ciofani A, Michie AM, Cuburu N, Aublin N, Maryanski JL, and Zuniga-Pflucker JC. (2004) Obligatory role for cooperative signaling by pre-TCR and Notch during thymocyte differentiation. J Immunol. 172:5230-5239.

Okada H, Bakal C, Shahinian A, Elia A, Wakeham A, Suh WK, Duncan GS, Ciofani M, Rottapel R, Zuniga-Pflucker JC, and Mak TW. (2004).Surviving Loss in Thymocytes Triggers p53-mediated Growth Arrest and p53-independent Cell Death. J Exp Med. 199:399-410.

Haks MC, Belkowski SM, Ciofani M, Rhodes M, Lefebvre JM, Trop S, Hugo P, Zuniga-Pflucker JC, Wiest DL. (2003). Low activation threshold as a mechanism for ligand-independent signaling in pre-T cells. J Immunol.. 170:2853-2861.