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Engineered t cells expressing carbohydrate recognition domain of ArtinM lectin to activate macrophages and treat cryptococcosis

Grant number: 16/23044-1
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): May 22, 2017
Effective date (End): May 21, 2018
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Maria Cristina Roque Antunes Barreira
Grantee:Thiago Aparecido da Silva
Supervisor abroad: Pappanaicken Kumaresan
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : University of Texas MD Anderson Cancer Center (MD Anderson), United States  
Associated to the scholarship:16/04877-2 - Design of new therapeutic strategies, based on the carbohydrate recognition, against cryptococcosis, BP.PD


T cell interaction with antigen presenting cell (APC), in which T-cell receptor (TCR) recognizes peptide-MHC complexes (p-MHC), is required to recruit downstream signaling molecules and trigger T cell activation. It was recently demonstrated that chimeric antigen receptor (CAR) expressed on T cells recognizes proteins, glycoproteins, and glycolipids as potential targets on cells surface, in a manner that does not depend on the MHC-fusion molecules. The construction of CARs is based on four segments, (i) an extracellular binding domain(s), (ii) a hinge or space region, (iii) a transmembrane region, and (iv) a cytoplasmic signaling region. Dr. Laurence J.N. Cooper's group studies in this field resulted in engineered CD19-specific CAR T cells that were employed in the treatment of B-cell malignancies to achieve a more efficient cancer control than the obtained with conventional therapy. Notably, a pioneer study that redirected CAR T-cells to recognize sugar, conducted in Dr. Cooper and Dr. Kumar laboratory, showed that those engineered cells exerted therapeutic effect against Aspergillus infection. Based on our own studies on the immunomodulatory activity of lectins that interact with TLR2 and/or TLR4 N-glycans, we have proposed to Dr. Kumar the construction of CAR T cells expressing carbohydrate recognition domain (CRD) of TLRs-binding lectins (lectin-CAR-T cells), such as ArtinM, Concanavalin A, and Wheat germ agglutinin. We hypothesize that these lectin-CAR-T cells may interact with TLR2 or TLR4, favoring the release of inflammatory mediators and inducing Th1 immunity. Since the collaborative proposal was accepted by Dr. Kumar, we planned to construct lectin-CAR-T cells, to evaluate the occurrence of M1 polarization of macrophages that interact with the engineered cells, and measure the fungicidal activity triggered by this interactive system against Cryptococcus gattii. The project is a high technology extension of our studies on driving immunity through carbohydrate recognition.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
KUMARESAN, PAPPANAICKEN R.; DA SILVA, THIAGO APARECIDO; KONTOYIANNIS, DIMITRIOS P. Methods of Controlling Invasive Fungal Infections Using CD8(+) T Cells. FRONTIERS IN IMMUNOLOGY, v. 8, JAN 8 2018. Web of Science Citations: 3.

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