Glycosaminoglycans in T cell activation and exhaustion

• Grant number: 19/05074-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2019
• End date: May 31, 2020
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Eloah Rabello Suarez
• Grantee: Eduardo Gonçalves Pereira
• Host Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil

Abstract

T cell exhaustion is a process characterized by progressive loss of T cell effector functions, associated with a decrease in cell proliferation rate, overexpression, and coexpression of several inhibitory receptors, despite other metabolic changes. Several tumors overexpress molecules that promote immune checkpoint blockade as a strategy to curb the immune response against cancer, such as the programmed cell death ligand 1 (PD-L1). The interaction of PD-L1 with the programmed cell death receptor 1 (PD-1), located on the T cell membrane, can promote the exhaustion of these cells. A recent study showed that heparan sulfate proteoglycans (HSPGs) - molecules formed by linear heteropolysaccharides called glycosaminoglycans (GAGs), associated with a protein core - favor the presentation of antigens to T cells and behave as co-receptors during the stimulation of these cells. This project aims to understand whether GAGs from cells in contact with T cells or from T cells, themselves could influence the exhaustion process. For this purpose, T cells will be activated and co-cultured with Chinese hamster ovary (CHO) cells presenting high or low expression of GAGs (CHO-K1 and pgsA-745, respectively) and T cell exhaustion will be assessed. In parallel, the treatment of T cells with a low dose of an inhibitor of GAG synthesis (4-methylumbelliferone) will also be performed to verify the direct effect of the chemical depletion of GAGs on T cells exhaustion. The analysis of exhaustion markers (PD-1, Tim-3, LAG-3), secretion of proinflammatory cytokines (IL-2 and IFN-³) and T cell proliferation assays will be used to verify exhaustion status in the different experiments. A better understanding of mechanisms enrolled in T cell exhaustion can be useful to improve therapy against cancer.