Biology subjects

Acevedo, G. R.

Publications and source records attributed to Acevedo, G. R..

3 recordsLinked to original sources

bioRxiv2025

Inhibitory NK receptors regulate the γδ T cell response to malaria

Gamma delta ({gamma}{delta}) T cells are important mediators of the immune response to childhood malaria infection. Human V{gamma}9+V{delta}2+ T cells possess intrinsic, HLA-independent responsiveness to Plasmodium falciparum phosphoantigens produced in the blood stage of malaria infection. Engagement of the {gamma}{delta} T cell receptor (TCR) by phosphoantigen-bound butyrophilin molecules results in V{gamma}9+V{delta}2+ T cell expansion, pro-inflammatory cytokine production, and release of cytotoxic granules that mediate parasite killing. Repeated malaria infection, however, leads to a reduction in circulating V{gamma}9+V{delta}2+ T cells and upregulation of immunomodulatory molecules, including NK receptors, that correlates with less severe symptoms upon infection. We explore phenotypic and functional differences of {gamma}{delta} T cells in Ugandan children with high versus low malaria exposure, utilizing high-parameter spectral flow cytometry analysis of PBMCs. We observed significant differences in expression of inhibitory NK receptors - KIR2DL1, KIR2DL2/3, KIR3DL1, LILRB1, and NKG2A - on {gamma}{delta} T cell subsets, with V{gamma}9+V{delta}2+ T cells exhibiting a divergent mechanism of control compared to other subsets. We found that NKG2A and KIR3DL1 expression associated with potent V{gamma}9+V{delta}2+ T cell responses to TCR- and Fc receptor (FcR)-mediated stimulation while KIR2DL1, KIR2DL2/3 and LILRB1 associated with reduced degranulation and cytokine production. These results identify a new role for inhibitory NK receptors expressed on {gamma}{delta} T cells, exerting a finely tuned balance of activating and inhibitory signals to regulate the response to malaria-related antigens. AUTHOR SUMMARYMalaria remains one of the deadliest infectious diseases, disproportionately affecting young children in sub-Saharan Africa who succumb to sequelae of Plasmodium falciparum infection. However, children living in highly endemic areas experience repeated malaria infection and develop naturally acquired-but not sterilizing-immunity which leads to an asymptomatic reinfection pattern. The immune factors that determine the balance of inflammatory and tolerogenic functions seen in non-sterilizing malaria immunity are yet to be fully understood. Here, we focus on the phenotypic and functional differences in one cell type between children with a history of low versus high malaria exposure. We identified a group of inhibitory surface receptors that improved the antimalarial function of this cell, and another group that worsened their function. Our study clarifies the immune landscape in highly malaria-exposed individuals and illuminates one potential system of regulating the cellular response to repeat infection.

immunology↗

bioRxiv2025

Learned Geometry, Predicted Binding: Structurally-BasedPrediction of Peptide:MHC Binding Using AlphaFold 3 EnablesCD4 T Cell Epitope Prediction

The accurate prediction of T cell epitope peptides within proteins of interest has a wide range of applications, but is complicated by the multiple determinants of antigenicity, the polymorphism of the Major Histocompatibility Complex (MHC) locus, and the great diversity of possible peptide antigens. Leading in silico methods use a variety of statistical approaches to learn from sequences identified through both in vitro MHC binding and peptide elution studies, but their performance remains imperfect, particularly for MHC II-restricted responses. Here we present MHCIIFold-GNN, an entirely orthogonal solution to this problem that combines three new elements: (i) a highly-multiplexed peptide:MHCII binding assay, (ii) generalizable structural modeling using AlphaFold3, and (iii) transfer learning with a Graph-based Neural Network. Trained exclusively on newly-generated in vitro binders, we show that MHCIIFold-GNN enables state-of-the-art prediction of CD4 T cell epitopes presented by diverse MHC II proteins, on par with non-structural methods that rely on much larger datasets including naturally-processed ligands. Moreover, when MHCIIFold-GNN and a leading non-structural method are combined, we observe unparalleled performance on a held-out test set (11 % boost), underscoring the orthogonality of the methods. These results highlight the power of a new class of structure-informed approaches to the CD4 T cell epitope prediction problem.

bioinformatics↗

bioRxiv2019

Altered frequency of CD24highCD38high transitional B cells in patients with cardiac involvement of chronic Chagas disease.

The cardiomyopathy developed by patients with chronic Chagas disease (CCD), one of the most severe consequences of T. cruzi infection, is mainly associated with an imbalance between an excessive inflammatory reaction and a defective immunomodulatory profile cause by host-parasite interaction. Despite the growing importance of the regulatory function of B-cells in many malignancies, few studies have addressed their immunosuppressive role in chronic Chagas disease. In this work, we tackled this issue by studying the proportion of different B cell subpopulations and their capacity to secrete IL-10 in individuals with distinct clinical forms of CCD. Seven-colour flow cytometry was performed to examine the peripheral blood B cell compartment in chronic Chagas disease (CCD) patients with and without cardiac manifestations (n=10 for each group) and non-infected donors (n=9). Peripheral blood mononuclear cells (PBMC) were incubated for 5h with PMA, ionomicyn and brefeldin A. According to the expression of markers CD19, CD24 and CD38, we showed an expansion of total B cell and transitional CD24highCD38high B cell subsets in CCD patients with cardiac involvement compared to non-infected donors. Furthermore, although no differences were observed in the frequency of total IL-10 producing B cells (B10) among the groups, CCD patients with cardiac involvement showed a statistically significant increased proportion of naive B10 cells and a tendency to an increased frequency of transitional B10 cells compared to non-infected donors. These findings suggest that immature transitional CD24highCD38high B cells are greatly expanded in patients with the cardiac form of chronic Chagas disease and these cells retain their ability to secrete IL-10 compared to non-infected donors. Furthermore, the distribution of naive, transitional and memory B cells inside the B10 cells followed the same pattern in chronic patients without cardiac involvement and non-infected individuals. Our work provides insight into the phenotypic distribution of regulatory B cell in CCD, an important step towards new strategies to prevent cardiomiopathy associated with T. cruzi infection.

immunology↗