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Fabio Santori
Postdoctoral Fellow
Ph.D. Sao Paulo School of Medicine 1996
santof01@popmail.med.nyu.edu

My major interest is focused on the mechanism of action of the orphan nuclear receptor ROR gamma-t, which has key roles in the development of lymphoid tissue inducer cells (Lti), Lti-like cells, thymocytes and pro-inflammatory Th17 cells . Lti cells are required for the formation of lymphoid tissues during fetal life and Lti-like cells are required for development of cryptopatches and other lymphoid structures in the lamina propria of the small intestine in adult animals. However, it is as regulators of Th17 cell development that RORgt has gained most prominence in recent years. Th17 cells are a subset of CD4+ T cells involved in severe inflammatory immune responses, autoimmune diseases and control of fungal and bacterial infections. The identification of natural ligands for RORgt is a fundamental step in the understanding on how this transcription factor is regulated and which metabolic processes are involved in the development of the Lti and T cell lineages that play such important roles in the immune system.
 
Ligands for nuclear hormone receptos (NHRs) are generally small lipophilic molecules that induce a conformational change in the ligand binding domain (LBD), allowing the recruitment of transcriptional coactivators and transcription of target genes. Examples of known ligands for specific members of the NHR superfamily include thyroid hormones (thyroid hormone receptor), steroid hormones (estrogen and androstane receptors), vitamin D (Vitamin D receptor) and retinoic acids (retinoic acid receptors). RORgt remains an orphan receptor with no known natural ligand.
 
To identify natural ligands (or pathways involved in their synthesis) for RORgt we are using several strategies, including the effect of gene overexpression or knockdown on transcriptional reporter systems in both mammalian and insect cells, use of medicinal chemistry to define important structural requirements for activity, and detection of putative ligands in tissues by HPLC, gas chromatography/mass spectrometry and nuclear magnetic resonance (NMR). Molecules and metabolic pathways identified by these strategies can then be tested for their role in the differentiation of Th17 cells and Lti cells.    
 

Publications

Santori, F.R. Immune responses induced by recombinant proteins based on the sequence of the 82-kDa surface antigen of Trypanosoma cruzi metacyclic tripoamstigotes. Sao Paulo, 1996. [Ph.D. Thesis, Escola Paulista de Medicina, Sao Paulo, Brazil].

Santori, F.R., Paranhos-Bacalla, G.S., Franco da Silveira, J., Yamauchi, L.M., Araya, J.E. & Yoshida, N. (1996). A recombinant protein based on Trypanosoma cruzi metacyclic trypomastigote 82 kDa antigen that induces an effective immune response to acute infection. Infect. Immun. 64(4): 1093-1099.

Santori, F.R., Dorta, M.L., Juliano, L., Juliano, M.A, da Silveira, J.F., Ruiz, R.C. & Yoshida, N. (1996). Identification of a domain of Trypanosoma cruzi metacyclic trypomastigote surface molecule gp82 required for attachment and invasion of mammalian cells. Mol. Biochem. Parasitol., 78(1-2): 209-216.

Santori, F.R., Lilic, M. & Vukmanovic, S. (1999). Assembly of the MHC Class I and its novel physiological role in the immune system. Rec. Res. Dev. Immunol., 1(2): 513-524.

Nesic, D., Santori, F.R. & Vukmanovic, S. (2000). abTCR+ cells are a minimal fraction of peripheral CD8+ pool in MHC Class I-deficient mice. J. Immunol., 165: 1896-1901.

Vukmanovic, S., Lilic, M., Santori, F.R., Demaria, S., & Kulig, K. (2001). Peptide loading of nascent MHC class I molecules. Arch Immunol Ther Exp (Warsz); 49(3):195-201.

Santori, F.R., Arsov, I. & Vukmanovic, S. (2001). Modulation of CD8+ T cell response to antigen by levels of self MHC class I. J. Immunol.; 166(9):5416-21.

Santori, F.R., Brown, S., Lu, Y., Neubert, T. & Vukmanovic, S. (2001). Positive selection induced by a self peptide with TCR antagonist activity. J Immunol.; 167(11):6092-5.

Nesic, D., Maric, M., Santori, F.R. & Vukmanovic, S. (2002). Factors influencing the patterns of T lymphocyte allorecognition. Transplantation; 73(5):797-803.

Santori, F.R., Arsov, I., Lilic, M. & Vukmanovic, S. (2002). Editing autoreactive TCR enables efficient positive selection. J. Immunol.; 169(4):1729-34.

Santori F.R., Kieper W., Brown S., Lu Y., Neubert T., Johnson K., Naylor S., Vukmanovic S., Hogquist K., Jameson S. (2002). Rare, structurally homologous self-peptides promote thymocyte positive selection. Immunity, 17(2):131-142.

Lilic M., Santori, F.R., Nielson, E.G., Frey, A.B., Vukmanovic, S. (2002). The role of fibroblasts in positive selection of T cells. J. Immunol., 169(9):4945-50.

Santori, F.R., Brown, S.M., Vukmanovic, S. (2002). Genomics- based identification of self-ligands with T cell receptor-specific biological activity. Immunol. Rev.; 190: 146-160.

Vukmanovic, S. Neubert, T.A. & Santori, F.R. (2003). Could T cell receptor antagonism explain associations between Major Histocompatibility Complex genes and disease? Trends Mol. Med. 9: 139-46.

Chen, Y., Dabovic, B., Colarossi, C., Santori, F.R., Lilic, M., Vukmanovic, S. & Rifkin, D.B. (2003). Growth retardation as well as spleen and thymus involution in latent TGF-b binding protein (Ltbp)-3 null mice. J. Cell Physiol., 196: 319-25.

Santori, F.R., Holmberg, K., Ostrov, D., Gascoigne, N.R.J.& Vukmanovic, S. (2004) Distinct footprints of TCR engagement with highly homologous ligands. J. Immunol., 172: 7466-7475.
Santori, F.R. & Vukmanovic S. (2004). Delineation of signals required for thymocyte positive selection. J. Immunol., 173: 5517-23.

Demaria, S., Santori, F.R., Ng, B., LLiebes, L., Formenti, S.C., & Vukmanovic, S. (2005). Select forms of tumor cell apoptosis induce dendritic cell maturation. J. Leukoc. Biol., 77:361-8.

Vukmanovic S. & Santori, F.R. (2005). Self-peptide/MHC and TCR antagonism: physiological role and therapeutic potential. Cell Immunol., 233: 75-84.

Santori, F.R., Popmihajlov, Z., Badovinac, V.P., Smith, C., Radoja, S., Vollmer, A., Harty, J.T., & Vukmanovic, S. (2007). TCR beta chain that forms peptide-independent alloreactive TCR transfers reduced reactivity with irrelevant peptide/MHC complex. J. Immunol., 178:6109-14.