Characterization of the cytotoxic profile of CD4+ T lymphocytes in multiple sclerosis

• Grant number: 23/14736-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: April 14, 2024
• End date: April 13, 2025
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Alessandro dos Santos Farias
• Grantee: Natália Munhoz Alves
• Supervisor: Jean Pierre Schatzmann Peron
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: University of Massachusetts Medical School (UMMS), United States
• Associated to the scholarship: 20/15500-2 - Evaluation of the cytotoxic activity of CD4+ T cells over oligodendrocytes in Multiple Sclerosis, BP.DD

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) whose pathogenesis involve autoreactive T cells crossing the blood-brain barrier, leading to neuroinflammation and demyelination. Whereas T CD4+ lymphocytes play a critical role in MS secreting inflammatory cytokines, CD8+ lymphocytes have a direct cytolytic effect on oligodendrocytes. The cytotoxic CD4+ T cells (CD4 CTLs), recognized for their cytotoxic potential in tumor immunity and viral infections, are also associated with MS severity, potentially targeting oligodendrocytes (OLs) and inducing tissue injury. Conversely, elevated levels of granzyme B (GzmB), a cytotoxicity-related serine protease, were found in relapse remitting MS (RRMS) patients' cerebrospinal fluid (CSF), and the expression of GzmB was observed in encephalitogenic CD4+ T cells in the experimental autoimmune encephalomyelitis (EAE) model. We have also demonstrated that CD4+ T cells from EAE mice induce apoptosis on healthy brain tissue and the cytotoxic activity is prominent in peripheral blood of patients in the early stage of RRMS. However, the precise characterization and the overall cytotoxic activity of CD4 CTLs during MS remain elusive. Hence, we aim to deeply characterize the CD4 CTL population in peripheral blood mononuclear cells (PBMCs) of RRMS patients through a combination of flow cytometry and RNA-seq techniques, to determine the transcriptional profile and surface markers. We will also investigate the soluble factors that are determinant for this cytotoxic profile, as well as the production of cytokines and the lysis of target cells. We further plan to delve deeper into the dissection of the biology of this T cell population using the experimental model (EAE), assessing the cytotoxic activity of CD4+ CTLs on oligodendrocytes.