Evaluation of the role of tissue repair Regulatory T cells during acute Trypanosoma cruzi infection

S BOCCARDO; CL ARAUJO FURLAN; C RODRIGUEZ; CP ABRATE; L ALMADA; A GRUPPI; CL MONTES; EV ACOSTA RODRIGUEZ

Mar del Plata

Congreso; REUNIÓN CONJUNTA SAIC SAI&FAIC SAFIS 2022; 2022

T. cruzi (Tc) and the type I response required to control it promote damage in target tissues. Tissue repair regulatory Foxp3+ CD4+ T cells (trTreg) are defined as ST2+ KLRG-1+ and specialized in maintaining tissue homeostasis and favoring repair upon injury in addition to their immunoregulatory properties. We aimed to study trTregs role in damage control during acute Tc infection. To this end, Foxp3-GFP C57BL/6 mice were infected (INF) with 5000 Tc parasites (Tulahuen). Skeletal muscle, liver and spleen (Sp) infiltrate was evaluated by flow cytometry in a kinetic study. trTregs were reduced in all tissues at 21 days post infection (dpi) in correlation with maximum tissue damage and parasitism, and decreased systemic levels of their growth factor IL33 (p<0.05). Recombinant IL33 allowed the in-vitro expansion of trTregs among sorted Tregs from INF Sp, but at 12, 15 and 18 dpi in mice. To identify signals that could counteract IL33 effect in-vivo, we cultured Tregs from non-INF Sp with IL33 plus IFNg/TNF/IL18, parasites or INF Sp conditioned media. In all cases, trTregs expanded normally. As IL33 could expand trTregs in non-INF mice, we treated INF mice at early dpi (0, 3 and 6) and evaluated disease evolution. This treatment resulted in increased trTreg in all tissues (p<0.05) lower levels of plasma LDH, CPK, GOT and Glucose and reduced body weight loss and tissue parasitism at 21 dpi. These was accompanied by an increase of Tc-specific CD8+ T cells and ILC2. We conclude that trTreg cell response is compromisedduring acute Tc infection likely because the inflammatory milieu is unfavorable for trTregs survival, preventing IL-33-mediated rescue. Yet, early IL-33 treatment improves the course of the acute infection. As trTregs and effector immune cells are increased by IL-33, further studies are required to establish the underlying mechanisms in the IL-33 protective effects.