Biology subjects

Gatti, L.

Publications and source records attributed to Gatti, L..

3 recordsLinked to original sources

bioRxiv2026

Platform-Imprinted Transcriptional and Clonal Remodeling of αβ and γδT Cells After Allogeneic Transplantation

Immune reconstitution after allogeneic hematopoietic stem cell transplantation is influenced by graft-composition and viral reactivation, but the combined long-term impact on {beta} and {gamma}{delta}T cells remains unclear. We analyzed a cohort of 213 patients receiving either {beta}T cell-depleted grafts (n=146; graft engineering that removes donor {beta}T cells) or T cell-replete grafts (n=67; containing donor T cells). Longitudinal immune phenotyping was integrated with bulk and single-cell TCR repertoire and transcriptomic profiling. CMV reactivation was associated with expansion of CD8+ {beta}T cells across both transplant types and with numerical dominance of V{delta}2- {gamma}{delta}T cells specifically in {beta}T cell-depleted recipients. V{delta}2- {gamma}{delta}T cells underwent early polyclonal expansion followed by repertoire focusing, independent of CMV, whereas {beta}T cells remained clonally restricted. Reduced early V{delta}2+ {gamma}{delta}TCR diversity was associated with EBV reactivation. Single-cell and TCR tracking analyses revealed long-term persistence of donor-derived V{delta}2+ {gamma}{delta}TCRs, whereas V{delta}1+ {gamma}{delta} and {beta}T cell repertoires were predominantly rebuilt de novo. Despite de novo rebuilding, {beta}TCR repertoire diversity diverged by platform at one year: {beta}T cell-depleted recipients exhibited marked (hyper)expansion of {beta}TCR clonotypes and lower diversity than T cell-replete recipients, indicating a durable imprint of graft engineering on {beta}TCR-clonality. Transcriptomic profiling showed that post-transplant T cells predominantly adopted effector programs, with platform-dependent polarization toward cytotoxic signatures in {beta}T cell-depleted recipients and toward AREG-associated tissue-repair signatures in T cell-replete recipients, consistent with wound-healing functions. In conclusion, transplantation platforms imprint durable clonal and transcriptional remodeling of {beta} and {gamma}{delta}T cells, while viral reactivation primarily amplifies expansion without fundamentally reshaping repertoire architecture. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/704768v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@88f136org.highwire.dtl.DTLVardef@944f13org.highwire.dtl.DTLVardef@d3835corg.highwire.dtl.DTLVardef@5548ef_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Sensitivity to Vγ9Vδ2TCR T cells is imprinted after single mutations during early oncogenesis

V{gamma}9V{delta}2T cells have the unique ability to recognize a broad range of malignant transformed cells. The tumor targeting event involving BTN2A1 and BTN3A1 dimers on the tumor cell surface is critical, leading to full activation of the TCR. Although the molecular mechanisms governing TCR engagement and T cell activation are well-characterized, the role of V{gamma}9V{delta}2 T cells in cancer immune surveillance remains to be fully elucidated, particularly the mechanisms that enable these cells to discriminate between healthy and malignant cells at an early stage of malignant transformation. We employed two independent, genetically engineered step-wise mutagenesis models of human colorectal and breast cancer that mimic the transformation steps leading to tumor formation. We demonstrate that various single oncogenic mutations introduced into healthy organoids or cells, are sufficient to upregulate surface expressed BTN2A1 and enable V{gamma}9V{delta}2 TCR binding to tumor cells. However, full activation of T cells through a V{gamma}9V{delta}2TCR required additional subsequent phosphorylation of juxtamembrane (JTM) amino acids of BTN3A1, leading to the activating heterodimerization of BTN2A1 and 3A1. Using a protein interactome mapping pipeline, we identified PHLDB2, SYNJ2 and CARMIL1 as key players in controlling these delicate dual surface dynamics of BTN2A1 and 3A1 during early transformation. This mode of action allowed V{gamma}9V{delta}2TCR T cells to control tumors in vitro and in vivo, emphasizing the crucial role of these molecules from early mutagenesis, to advanced cancer stages, and highlighting the therapeutic potential of a V{gamma}9V{delta}2TCR.

cancer biology↗

bioRxiv2017

Cross-reactive immunity drives global oscillation and opposed alternation patterns of seasonal influenza A viruses

Several human pathogens exhibit distinct patterns of seasonality and circulate as pairs of discrete strains. For instance, the activity of the two co-circulating influenza A virus subtypes oscillates and peaks during winter seasons of the worlds temperate climate zones. These periods of increased activity are usually caused by a single dominant subtype. Alternation of dominant strains in successive influenza seasons makes epidemic forecasting a major challenge. From the start of the 2009 influenza pandemic we enrolled influenza A virus infected patients (n = 2,980) in a global prospective clinical study. Complete hemagglutinin (HA) sequences were obtained from 1,078 A/H1N1 and 1,033 A/H3N2 viruses and were linked to patient data. We then used phylodynamics to construct high resolution spatio-temporal phylogenetic HA trees and estimated global influenza A effective reproductive numbers (R) over time (2009-2013). We demonstrate that R, a parameter to define host immunity, oscillates around R = 1 with a clear opposed alternation pattern between phases of the A/H1N1 and A/H3N2 subtypes. Moreover, we find a similar alternation pattern for the number of global virus migration events between the sampled geographical locations. Both observations suggest a between-strain competition for susceptible hosts on a global level. Extrinsic factors that affect person-to-person transmission are a major driver of influenza seasonality, which forces influenza epidemics to coincide with winter seasons. The data presented here indicate that also cross-reactive host immunity is a key intrinsic driver of global influenza seasonality, which determines the outcome of competition between influenza A virus strains at the onset of each epidemic season.\n\nSignificance statementAnnual influenza epidemics coincide with winter seasons in many parts of the world. Environmental factors, such as air humidity variation or temperature change, are commonly believed to drive these seasonality patterns. Interestingly, three out of the four latest pandemics (1918, 1968 and 2009) did not spread in winter initially, but during summer. This questions to what extent other factors could also impact virus spread among humans. We demonstrate that cross-reactive host immunity is a key factor. It drives the well-known seasonal patterns of virus activity oscillation and alternation of the dominant influenza virus subtype in successive seasons. Furthermore, this factor may also explain the efficient spread of pandemic viruses during summer when cross-reactive host immunity is relatively low.

epidemiology↗