D'Anniballe, V. | bioRxiv Science

bioRxiv2025

Olfactory biopsy analysis of Alzheimer's pathobiology across disease stages

Alzheimers Disease (AD) is a neurodegenerative condition affecting millions worldwide. Defining early pathobiological events remains challenging, in part due to inaccessibility of neural tissue. Because olfactory neurons are accessible, and olfactory loss is prevalent in AD, we evaluated olfactory brush biopsies from controls, individuals with cerebrospinal fluid (CSF) biomarker-confirmed AD, and cognitively typical individuals whose positive biomarkers signal a pre-clinical AD stage. We define via single cell RNA-sequencing (n=22 subjects) conserved neuroinflammatory T cell, myeloid, and olfactory neuron changes detectable even in pre-clinical AD subjects. Activated memory T cell states were a hallmark of pre-clinical AD, paralleling CSF T cell phenotypes seen in advanced disease, accompanied by both microglia-like inflammatory programs and olfactory neuron inflammatory injury. Together, our findings establish a novel platform permitting analysis of neural tissue in AD at its earliest stages.

neuroscience↗

bioRxiv2023

A Novel MHC-Independent Mechanism of Tumor Cell Killing by CD8+ T Cells

The accepted paradigm for both cellular and antitumor immunity relies upon tumor cell kill by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex class I (MHC I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8+T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent on interactions between T cell NKG2D and tumor NKG2D ligands (NKG2DL). Necessarily, tumor cell kill in these instances is antigen-independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumors cells. These mechanisms are active in vivo in mice, as well as in vitro in human tumor systems, and are obviated by NKG2D knockout or blockade. Tumor cell killing following T cell NKG2D engagement is Fas-independent and appears to involve granzyme. These studies potentially obviate the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape, and instead identify the NKG2D/NKG2DL axis as a novel therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC loss variants.

immunology↗