Biology subjects

Lanna, A.

Publications and source records attributed to Lanna, A..

4 recordsLinked to original sources

bioRxiv2026

Awakening intracellular immunity for functional HIV cure

HIV persists in long-lived CD4 T cell reservoirs despite antiretroviral therapy (ART)1. Elite controllers suppress viraemia without ART2, yet reservoir reactivation emerges with immune ageing3. Here we show that transient reprogramming of patient-derived CD4 T cells restores their ability to eliminate HIV-infected reservoirs, excising integrated proviral DNA. A defined compound, or physiological induction, drove rapid reprogramming ex vivo, enabling clearance of HIV DNA within hours to days of treatment, independently of ART. Single-cell RNA sequencing revealed activation of an antiviral telomere transfer programme4 that exceeds elite-like control. In humanised mice, adoptive transfer of reprogrammed patient CD4 T cells, or in vivo reprogramming of murine T cells, eliminated HIV DNA across reservoirs, with undetectable viral genomes persisting for months. Modelling predicted that residual proviral reactivation would be governed by rare stochastic events, rendering viral rebound unlikely within a human lifespan. These findings identify a previously unrecognised form of intracellular immunity and establish a defined route to a functional HIV cure arising from the CD4 T cell itself.

immunology↗

bioRxiv2025

CD4⁺ T cells confer transplantable rejuvenation via Rivers of telomeres

The role of the immune system in regulating organismal lifespan remains poorly understood. Here, we show that CD4 T cells release "telomere Rivers" into circulation after acquiring telomeres from antigen-presenting cells (APCs). River formation requires fatty acid oxidation at the T cell-APC synapse, which selectively excludes glyceraldehyde 3-phosphate dehydrogenase (GAPDH) from the telomere vesicles. The resulting Rivers are depleted of glycolytic enzymes but enriched in T cell-derived stemness factors, enabling targeted rejuvenation of senescent tissues across multiple organs. In aged mice, adoptive transfer of young or metabolically reprogrammed CD4 T cells triggered River production in vivo, and Rivers isolated from these animals could be transplanted into other aged mice to propagate the rejuvenation phenotype independently of T cells. River therapy extended median lifespan by [~]17 months, with several mice surviving to nearly five years. This immune-driven telomere transfer pathway is conserved across kingdoms, including plants, defining the first systemic, transplantable programme of youth.

cell biology↗

bioRxiv2024

Disruptors of sestrin-MAPK interactions rejuvenate T cells and expand TCR specificity

Whereas treatments that reactivate exhausted T cells are available, strategies to rejuvenate terminally differentiated senescent lymphocytes are yet to be developed. Senescent T cells, with short telomeres and inactive telomerase, are different from exhausted cells, and may form due to defective telomere transfer reactions upon contact with antigen presenting cells (APCs). Senescent T cells are characterized by presence of sestrin-MAPK kinase activation complexes (sMACs), large immune-inhibitory protein assemblies of sestrins bound to a stress/energy sensing kinase (AMPK) and three functional effector kinases (ERK, JNK and p38 MAPKs). Here we described first in class Disruptors of the Sestrin-MAPK immune-inhibitory Complex (DOS), which target sMAC to ubiquitin-dependent proteasomal degradation, resulting in long-term sestrin transcriptional inhibition, increased T cell fitness, and generation of long-lived stem like memory features. Strikingly, the DOS generated stem T cells present de novo antigen-specific T-cell receptor DNA rearrangements that precede their future expansion. Although largely senescent at the point of treatment, the DOS regenerated T cells, with stem features and new TCRs, initiated immune-protective rejuvenation-dependent responses to new challenges, with or without vaccination. Therefore, it is possible to generate new T cell clones from formerly senescent cells and expand immune specificity. HighlightsO_LIDOS are the first sestrin-MAPK binding disruptors C_LIO_LIDOS rejuvenate T cells (DOS-juvenation) C_LIO_LIDOS-juvenated T cells protect old mice from lethal infections, with or without vaccination C_LIO_LIDOS-juvenated T cells exist as stem-like cells that undergo antigen-specific TCR revisions C_LI

immunology↗

bioRxiv2020

Intercellular telomere transfer extends T cell lifespan

The common view is that T-lymphocytes activate telomerase, a DNA polymerase that extends telomeres at chromosome ends, to delay senescence. We show that independently of telomerase, T cells elongate telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs). Upon contact with T cells, APCs degraded shelterin to donate telomeres, which were cleaved by TZAP, and then transferred in extracellular vesicles (EVs) at the immunological synapse. Telomere vesicles retained the Rad51 recombination factor that enabled them to fuse with T cell chromosomal ends causing an average lengthening of [~]3000 base pairs. Thus, we identify a previously unknown telomere transfer program that supports T cell lifespan.

immunology↗