# Architecture and interactions of Granzyme K+ CD8 T cells in inflamed synovium in rheumatoid arthritis

> **NIH NIH K08** · UNIVERSITY OF COLORADO DENVER · 2024 · $167,875

## Abstract

Project Summary/Abstract
This proposal is a five-year research and training plan with a scientific focus on interactions between CD8 T
cells and fibroblasts in synovial tissue from patients with rheumatoid arthritis (RA). We have found that the
majority of CD8 T cells in RA synovium have an unusual phenotype characterized by low expression of classic
cytotoxic proteins such as granzyme B, perforin, and granulysin. Instead, these cells express high amounts of
granzyme K, which induces synovial fibroblasts to produce pro-inflammatory factors such as IL-6. Based on
our preliminary data, we believe that granzyme K does more than simply activate synovial fibroblasts. We
believe that granzyme K activates the complement system to induce so-called inflammatory priming of synovial
fibroblasts, characterized by metabolic reprogramming and augmented activation to stimuli.
The specific aims proposed here will investigate the interactions of CD8 T cells and synovial fibroblasts in three
complementary ways. Aim 1 interrogates whether human granzyme K induces the metabolic reprograming
associated with inflammatory priming and whether complement mediates the downstream effects of granzyme
K. Aim 2 uses imaging mass cytometry, traditional immunofluorescence, and spatial transcriptomics to
evaluate granzyme K+ CD8 T cells and their relationship with fibroblast subsets and complement deposition
within the context of human synovial tissues. Aim 3 uses mouse models of inflammatory arthritis to determine
the effects of granzyme K on clinical and cellular measures in inflammatory arthritis.
This study combines mechanistic studies, patient-derived samples, mouse models, and cutting-edge
transcriptomic technologies to provide the candidate new training in several key aspects of translational
immunology. The candidates immediate career development goals are to gain experience with microscopy
techniques, spatial transcriptomics, cellular metabolism, mouse models of autoimmune diseases, and
bioinformatic analysis. A specific career development plan is described by both the candidate and her mentor
Dr. Michael Brenner, MD, an expert in lymphocyte biologic and synovial inflammation. She also has the
support of an Advisory Committee of experts in the areas in which she will build her skills. The candidate’s
long-term goal is to attain a tenure-track faculty position pursuing research that integrates high-dimensional
analysis of patient samples with detailed mechanistic studies to characterize cellular interactions within tissues
in rheumatologic diseases, with the ultimate goal of identifying new cellular and molecular candidates for
diagnosis and treatment of autoimmune diseases.

## Key facts

- **NIH application ID:** 10993153
- **Project number:** 5K08AR081412-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Anna Helena Jonsson
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $167,875
- **Award type:** 5
- **Project period:** 2023-08-31 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10993153

## Citation

> US National Institutes of Health, RePORTER application 10993153, Architecture and interactions of Granzyme K+ CD8 T cells in inflamed synovium in rheumatoid arthritis (5K08AR081412-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10993153. Licensed CC0.

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