Characterization of cytotoxic CD4+ T cells response in health and disease

• Grant number: 25/02969-6
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2025
• End date: May 31, 2027
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Alessandro dos Santos Farias
• Grantee: Alessandro dos Santos Farias
• Principal researcher abroad: Jean Pierre Schatzmann Peron
• Institution abroad: University of Massachusetts Medical School (UMMS), United States
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 21/08354-2 - The interplay between the immune system and metabolism as a key determinant of the aging process, AP.TEM

Abstract

Classically, adaptive immunity is characterized by two types of responses: the humoral response, in which B cells are the leading players, and the cell-mediated immune response, controlled by activated T cells. In general, T lymphocytes are divided into CD4+ and CD8+, with helper and cytotoxic activities, respectively. Further research, however, showed that CD4+ can also be cytotoxic under special conditions. Although this characteristic was described about 50 years ago, this concept remained dormant. The last decade has seen the revisitation of this concept through several studies especially in the context of virus infection, tumorigenesis and aging. Noteworthy, CD4+ Cytotoxic T Lymphocytes (CTLs), are also found in healthy individuals and increased in supercentenarians (individuals over 110 years of age), a feature that, according to the author, "may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases". Thus, while on one hand, CD4-CTLs confer defense against infections and avoid the growth of tumors, on the other hand, they may be linked to autoimmune pathology, worsening the subject's quality of life. Recently, our group has also demonstrated an enhanced cytotoxic activity of B and CD4+ T cells in autoimmune diseases, particularly Multiple Sclerosis (MS). MS is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The strongest genetic risk factor associated with MS lies within the major histocompatibility complex (MHC) class II locus, which supports the central role of T helper (Th) cells in the pathogenesis of MS. Experimental autoimmune encephalomyelitis (EAE), an established animal model of MS, can be induced by the adoptive transfer of CD4+ T cells specific to the neuroantigen. Although the inflammatory activity of these cells is well known, the mechanisms through which encephalitogenic CD4+ T cells initiate tissue lesions are not fully comprehended. It is unclear whether these cells promote direct cytolytic activity against the target tissue or if they solely create an inflammatory environment, thereby allowing other leukocytes to enter the CNS and exert their effector function. Therefore, we believe that determining how CD4-CTLs acquire cytotoxic activity and how it correlates with MS pathology, is key to unravel unappreciated new signaling pathways with great translational potential. (AU)