Biology subjects

Donovan, M. G.

Publications and source records attributed to Donovan, M. G..

2 recordsLinked to original sources

bioRxiv2026

Progressive deterioration of adaptive immune repertoires in Down syndrome linked to interferon hyperactivity and lymphoid tissue disorganization

Persons with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display strong dysregulation of adaptive immunity, which underlies high risk of complications from infections, widespread autoimmunity, and poor vaccine responses. However, the mechanisms by which T21 dysregulates adaptive immunity across the lifespan remain poorly understood. We report here a multimodal analysis of adaptive immunity across development and aging in DS, including deep B cell profiling by mass cytometry matched to transcriptome and proteome data, B and T cell receptor sequencing (BCR, TCR), and spatial transcriptomics of tonsil tissue. T21 causes progressive shifts in B cell subsets together with accelerated age-dependent B cell loss linked to hyperactive interferon and JAK/STAT signaling. The peripheral immunoglobulin repertoire shows dysregulated class switching, progressive loss of diversity, differential VDJ usage, and imbalanced rates of somatic hypermutation across immunoglobulin isotypes mirrored by contraction and skewing of the TCR repertoire. In children with DS, tonsil tissues are highly disorganized with smaller germinal centers, fibrotic intrusions, lower rates of cell proliferation, strong inflammatory signaling, and transcriptional programs indicative of dysregulated lymphocyte homing and residence. Together, these results point to hyperactive interferon signaling as a driver of dysregulated adaptive immunity in DS amenable to early therapeutic intervention.

immunology↗

bioRxiv2022

Enhanced Effector Activity of Mediator Kinase Module Deficient CAR-T Cells

Adoptive T cell immune therapies mediate impressive clinical benefit in a fraction of patients, but anti-tumor effects are often limited by inadequate T cell potency. To identify genes limiting T cell effector function, we conducted genome-wide CRISPR knock-out screens in human primary CAR-T cells. The top hits were MED12 and CCNC, components of the cyclin-dependent kinase (CDK) module of the Mediator complex, an evolutionarily conserved regulator of gene transcription. MED12 or CCNC deficient CAR-T cells manifest increased expansion, cytokine production, metabolic fitness, effector function, anti-tumor activity and reduced terminal effector differentiation. Chemical inhibition of CDK8/19 kinase activity recapitulated some features of genetic loss of MED12, including increased T cell expansion. MED12 deficient CAR-T cells showed widespread but selective increases in chromatin accessibility, MED1 chromatin occupancy, and H3K27 acetylation at enhancers used by transcription factors playing a critical role in T cell fate, including several STAT and AP1 family members. The most pronounced enhancement was observed for STAT5 which manifested as increased sensitivity to IL-2 in MED12 deficient T cells. These results link Mediator induced transcriptional coactivation with T cell effector programming and identify the CDK module as a target for enhancing the potency of anti-tumor T cell responses. One Sentence SummaryThe Mediator kinase module is a primary regulator of T cell differentiation, and genetic or small molecule-based inhibition of this module enhances effector T cell potency.

immunology↗