Biology subjects

Chiu, B. C.

Publications and source records attributed to Chiu, B. C..

3 recordsLinked to original sources

bioRxiv2026

Maintenance of immune tolerance during aging requires competitive expansion of memory phenotype regulatory T cells

Memory phenotype (MP) CD4+ T cells accumulate with age; however, the immunological significance of this population shift and the mechanisms that preserve MP T-cell fitness remain poorly understood. Here, we show that age-associated accumulation of MP T cells is regulated by intra-clonal competition and that competitive expansion of MP regulatory T (Treg) cells is required for maintenance of immune tolerance during aging. Using MLL1 deficiency as a model, we found that Mll1-deficient T cells failed to undergo normal age-associated accumulation and were progressively outcompeted by wild-type (WT) cells despite retaining the ability to proliferate and generate MP populations in the absence of competitors. Mechanistically, MLL1 preserved competitive fitness by maintaining transcription of TCR variable region genes and sustaining T-cell receptor expression during proliferation. Loss of competitive fitness impaired MP Treg-cell expansion and disrupted immune homeostasis. Remarkably, a small population of WT Treg cells restored tolerance through extensive expansion of MP Treg cells. These findings identify competitive expansion of MP Treg cells as a critical mechanism for maintaining immune tolerance during aging.

immunology↗

bioRxiv2026

Lifelong self-renewal and competition shape the virtual memory CD8 T-cell compartment during aging

Primary CD8+ T-cell responses decline with age, increasing susceptibility to novel infections. Virtual memory (VM) CD8+ T cells are memory-phenotype cells that respond rapidly to infection and undergo marked expansion with age. Although aged VM cells exhibit functional impairment, cellular senescence, and clonal expansion, the mechanisms responsible for these changes remain poorly understood. Here, we show that the VM-cell compartment in aged mice is derived predominantly from cells generated early in life and maintained through continuous self-renewal. Over time, resident VM cells acquire increased competitive fitness, resulting in progressive enrichment of the resident population and exclusion of newly generated VM cells. Consequently, unlike the naive CD8+ T-cell compartment, which is continuously replenished throughout life, the VM-cell compartment becomes dominated by long-lived resident cells. Depletion of resident VM cells resets the aged VM-cell compartment and permits expansion of newly generated VM cells. These findings identify lifelong self-renewal and competition as key mechanisms shaping VM-cell aging.

immunology↗

bioRxiv2026

The MLL1-MENIN complex preserves CD8 T cell memory through a TOX-BTLA-TCF1 axis

Immunological memory depends on the maintenance of stem cell-like memory CD8 T cells, which require sustained expression of the transcription factors TCF1. Here, I identify MLL1 as a key regulator of CD8 T cell memory. In activated T cells, MLL1 sustains Tox transcription through interaction with MENIN, thereby maintaining BTLA expression and restraining cytokine-driven AKT activation. Loss of MLL1 or disruption of the MLL1-MENIN interaction accelerates AKT-driven loss of TCF1, leading to impaired memory potential. MLL1-deficient T cells fail to reconstitute lymphopenic hosts and are unable to mediate graft-versus-host disease, while exhibiting increased expansion of virtual memory T cells. Unexpectedly, MLL1 regulates Tox, Btla and Tcf7 independently of its methyltransferase activity and MOF-mediated H4K16 acetylation. These findings define a pathway in which the MLL1-MENIN complex restrains cytokine signaling to preserve CD8 T cell memory and identify a noncanonical function of MLL1 in transcriptional maintenance.

immunology↗