UNRAVELING METABOLIC AND MITOCHONDRIAL PATHWAYS IN T. CRUZI-SPECIFIC CD8 EFFECTOR T CELLS: EXPLORING POTENTIAL INTERVENTIONS

HELLRIEGEL, MF; BAIGORRÍ, RE; VAZQUEZ VIGNALE, M; FONTANARI, C; CERBAN, FM; STEMPIN, CC

San Luis

Congreso; LXXI Reunión Científica Anual de la Sociedad Argentina de Inmunología.; 2023

Sociedad Argentina de Inmunología

Trypanosoma cruzicauses Chagas' disease, endemic in Latin America andglobally present. The infection involves an acute phase (AP) with highparasitemia that transitions to chronic stage, potentially leading to Chagasicpathology. CD8 T cells are crucial for host resistance, but T. cruzispecificCD8+T cell (Tc-CD8) immunity develops slowly, with reduced breadthand may acquire dysfunctional features. Mitochondria plays a key role in CD8T cell immune response. Mitochondrial membrane potential (MMP) andmitochondrial superoxide (mROS) levels impact in effector function. Ourprevious results showed an increase in total CD8 T cells with depolarizedmitochondria (DM) and mROS during AP of BALB/c infection. Then, the aimof this study was to improve mitochondrial quality on CD8 T cells and exploreits impact on infection. To achieve this, Nicotinamide Riboside (NR), aprecursor to NAD+ and mitophagy inducer was used. BALB/c mice wereinfected (I) with 500 trypomastigotes from Tulahuen strain (tp-Tul). Noninfected (NI) animals were used as controls. Mice were treated with NR (500mg/kg/day by oral gavage) or PBS from 5-20 days post infection (dpi) (I-NRor I-PBS). Spleen cells were isolated at 21 dpi. We examined mitochondrialmass (MM), MMP and mROS production by FACS combining MMPdependent,MMP-independent mitochondrial dyes and MitoSOX respectively.We observed that I-NR mice with lower parasitemia levels exhibit betterbiochemical parameters in plasma. They also displayed a tendency todecrease in the frequency of effector (E) CD8+ T cells with DM and mROSproduction. Likewise, I-NR mice exhibited a higher frequency of IL-2-producing E CD8+ T cells. Moreover, we aimed to extend our investigation ofmitochondrial metabolism to Tc-CD8 T cells. Then, C57BL/6 mice wereinoculated with 5000 tp-Tul. Spleen cells were obtained at 9, 20 and 78dpi. Tc-CD8 T cell response was measured by FACS using tetramers loadedwith the parasite immunodominant peptide Tskb20 in E cells. Moreover,glucose uptake through 2-NBDG probe and expression of the glutaminetransporter CD98 was assessed by FACS. We observed that the peak ofparasitemia correlates with a higher number of total and E Tc-CD8 cells. Thesecells showed an increase in MMP at 9 dpi (p=0,05) while mROS productionand MM were higher at 20 dpi (p<0,05; p<0,0005) and these parametersdecreased at 78 dpi. Besides, glucose uptake and CD98 expression wereincreased at 20 dpi (p<0,0005; p<0,05). However, at this point of infection ahigh proportion of Tc-CD8 T cells lose MMP (p<0,05). These Tc-CD8 T cellswith DM showed less glucose uptake and reduced CD98 expression(p<0,0001; p<0,05). Our findings indicate that while Tc-CD8 T cells engagemetabolic and mitochondrial programs during infection, further research couldshed light on novel pathways that modulate the induction, maintenance, andregulation of CD8 T cell responses to T. cruzi. This insight might guide newstrategies to improve infection outcomes.