T lymphocytes exhaustion on Visceral Leishmaniasis

• Grant number: 24/04649-6
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2025
• End date: July 31, 2027
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Vanessa Carregaro Pereira
• Grantee: Vanessa Carregaro Pereira
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Fernando de Queiroz Cunha ; João Santana da Silva ; Luciana Benevides

Abstract

A key point of immunity against Leishmania protozoa parasites is the development of an optimal T cell response, which exhibits a low apoptotic rate, high proliferative potential and polyfunctionality, promoting the control of parasite replication. During the chronic inflammation, the functionality of specific T cells becomes lost, presenting an inferior effector functions, little responsive to specific restimulation and sub-optimal homeostatic proliferation, a term referred to as cell exhaustion. In human Visceral Leishmaniasis (VL) caused by L. infantum and in a murine model, it has been observed that T lymphocytes (CD4 and CD8) lose their functionality, inability to produce IL-2, proliferate and produce pro-inflammatory cytokines. Concomitant to their loss of function, the exhausted T cells exhibit increased apoptotic potential, promoting clonal deletion. Multiple factors, such as parasite load, duration of infection (acute or chronic) and parasite-host interaction may promote the exhaustion of T lymphocytes. These factors contribute to the constant presence of the antigen and promote the expression of inhibitory receptors ( CTLA-4, PD1, CD39, CD73, TIGIT, LAG-3 and TIM3), transcription factors (FOXP3, BLIMP-1) and sustained production of soluble mediators (IL-10, IL-27, IFN-I). We have demonstrated that parasites, mainly L. infantum, use some innate receptors to promote cellular exhaustion, providing a favorable microenvironment for the induction of inhibitory molecules, soluble mediators and subverting the immune response in the vertebrate host. Thus, the present project focuses on: 1) understanding the exhaustion of T lymphocytes in VL and the role of some mentioned inhibitory molecules involved in this process, 2) participation of the innate nucleic acid receptors, such as TLR7 (endosomal) and AIM2 (cytosolic) involved in the induction of inhibitory molecules through IFN-I-dependent mechanisms; 3) regulation between AIM2 and BLIMP-1 in the outcome of T lymphocyte response in experimental VL. We believe that these signals promote several changes, reprogramming cells to a quiescent state, influencing the disease progression. (AU)