Tracking the Immune Triggers of Rheumatoid Arthritis
Arthritis Foundation funds two teams of researchers to identify RA culprits.
By Vandana Suresh | Feb. 20, 2026
Through millions of years, our bodies have evolved to have a multiplicity of immune cell types to fight against pathogens and cancers. However, in autoimmune diseases, the immune system launches an unabated attack on the body’s own cells, tissues and organs. Identifying the primary immune culprits and their triggers of rheumatoid arthritis (RA), a common and devastating autoimmune disease, remains an ongoing quest.
To take a deeper dive into this question, the Arthritis Foundation has awarded an RA Research Program grant to Anna Helena Jonsson, MD, PhD, from the University of Colorado Anschutz, and Ayano Kohlgruber, PhD, from Boston Children’s Hospital. Using sophisticated molecular and genetic techniques, they will investigate the targets of a special type of immune cell, the CD8+ granzyme K-positive T cell, which is replete in joint tissue in RA, where it is thought to trigger inflammation and joint destruction.
“We are really delig
hted that the Arthritis Foundation decided to support early career investigators,” says Dr. Kohlgruber. “The Foundation’s support is essential for supporting ambitious and early-stage research that has the potential to grow into a much bigger project.”
Autoimmune diseases are primarily caused by the disruption of the adaptive immune cells, the T and B cells. However, there is a remarkable variety of these cell types. For example, although there are two main functional categories of T cells — the helper (CD4) and the cytotoxic (CD8) T cells — each encompasses numerous specialized subgroups. In recent years, research has revealed that CD8 subtypes are just as abundant as the more commonly studied CD4 subtypes in RA synovium. Further, Dr. Jonsson’s group has identified a more specialized type of CD8 T cell, positive for the granzyme K protein, that is enriched in the joint.
Typically, CD8 T cells circulate throughout the body, seeking virally infected cells and cancer cells. Their job is to act as assassins, so if they find a virally infected cell, like one infected with influenza or COVID-19, these T cells kill the infected cell to terminate the infection. But the CD8+ granzyme K-positive T cells are different.
“They are not the killer phenotype, but are rather more pro-inflammatory,” says Dr. Jonsson. “We think that there is a specific synovial protein that the CD8+ granzyme K-positive T cells recognize in RA, but we really have no idea what that is.”
Why would CD8+ granzyme K-positive T cells turn on healthy joint tissues? The researchers posit that these cells may have initially reacted to a virus, and years later, a harmless synovial protein might have had the misfortune of resembling a component of the virus that triggered an immune response. Thus, although these T cells initially responded only to viruses, they eventually began reacting to self-tissues. The researchers will test their hypothesis in the Arthritis Foundation-funded study.
Dr. Kohlgruber’s team will look for antigens or synovial proteins that could serve as targets for CD8 granzyme K-positive T cells. They will engineer synthetic T cells expressing receptors similar to those of granzyme K-positive T cells. They will also create target cells that present antigens to these synthetic T cells.
“When you mix these two cell populations, and the T cells recognize a protein out of tens of thousands that are presented, they will be marked biochemically,” says Dr. Kohlgruber. “We can then pull out those cells and perform next-generation sequencing to identify what peptides are triggering the T cells.”
Taking the research onward from this stage, Dr. Jonsson’s team will use state-of-the-art spatial transcriptomics to localize these antigen-specific T cells.
“This technique has been available now for two or three years, and everyone is really excited, because it allows us to put these cell types of interest in their actual position in the tissue,” says Dr. Jonsson. “Now we can also identify antigen-specific T cells using this technology. So, we can ask, are the antigen-specific T cells in the synovial lining? Are they next to blood vessels? So, where are they, and what are their cellular neighbors?”
If CD8 granzyme K-positive T cells are the leading players in RA, then CAR-T (chimeric antigen receptor-T) cell, CAR-Treg or mRNA vaccine therapy could potentially be considered as a means to turn off or dampen the autoimmune response.
“This is a very special kind of project; it cannot be done in tiny pieces. It has to be pursued as a greater, integrated effort,” says Dr. Jonsson. “We needed a funding mechanism willing to support something truly novel, including new technologies to explore entirely new questions. The Arthritis Foundation’s willingness to invest in that novelty was essential.”
Through millions of years, our bodies have evolved to have a multiplicity of immune cell types to fight against pathogens and cancers. However, in autoimmune diseases, the immune system launches an unabated attack on the body’s own cells, tissues and organs. Identifying the primary immune culprits and their triggers of rheumatoid arthritis (RA), a common and devastating autoimmune disease, remains an ongoing quest.
To take a deeper dive into this question, the Arthritis Foundation has awarded an RA Research Program grant to Anna Helena Jonsson, MD, PhD, from the University of Colorado Anschutz, and Ayano Kohlgruber, PhD, from Boston Children’s Hospital. Using sophisticated molecular and genetic techniques, they will investigate the targets of a special type of immune cell, the CD8+ granzyme K-positive T cell, which is replete in joint tissue in RA, where it is thought to trigger inflammation and joint destruction.
“We are really delig
hted that the Arthritis Foundation decided to support early career investigators,” says Dr. Kohlgruber. “The Foundation’s support is essential for supporting ambitious and early-stage research that has the potential to grow into a much bigger project.” Autoimmune diseases are primarily caused by the disruption of the adaptive immune cells, the T and B cells. However, there is a remarkable variety of these cell types. For example, although there are two main functional categories of T cells — the helper (CD4) and the cytotoxic (CD8) T cells — each encompasses numerous specialized subgroups. In recent years, research has revealed that CD8 subtypes are just as abundant as the more commonly studied CD4 subtypes in RA synovium. Further, Dr. Jonsson’s group has identified a more specialized type of CD8 T cell, positive for the granzyme K protein, that is enriched in the joint.
Typically, CD8 T cells circulate throughout the body, seeking virally infected cells and cancer cells. Their job is to act as assassins, so if they find a virally infected cell, like one infected with influenza or COVID-19, these T cells kill the infected cell to terminate the infection. But the CD8+ granzyme K-positive T cells are different.
“They are not the killer phenotype, but are rather more pro-inflammatory,” says Dr. Jonsson. “We think that there is a specific synovial protein that the CD8+ granzyme K-positive T cells recognize in RA, but we really have no idea what that is.”
Why would CD8+ granzyme K-positive T cells turn on healthy joint tissues? The researchers posit that these cells may have initially reacted to a virus, and years later, a harmless synovial protein might have had the misfortune of resembling a component of the virus that triggered an immune response. Thus, although these T cells initially responded only to viruses, they eventually began reacting to self-tissues. The researchers will test their hypothesis in the Arthritis Foundation-funded study.
Dr. Kohlgruber’s team will look for antigens or synovial proteins that could serve as targets for CD8 granzyme K-positive T cells. They will engineer synthetic T cells expressing receptors similar to those of granzyme K-positive T cells. They will also create target cells that present antigens to these synthetic T cells. “When you mix these two cell populations, and the T cells recognize a protein out of tens of thousands that are presented, they will be marked biochemically,” says Dr. Kohlgruber. “We can then pull out those cells and perform next-generation sequencing to identify what peptides are triggering the T cells.”
Taking the research onward from this stage, Dr. Jonsson’s team will use state-of-the-art spatial transcriptomics to localize these antigen-specific T cells.
“This technique has been available now for two or three years, and everyone is really excited, because it allows us to put these cell types of interest in their actual position in the tissue,” says Dr. Jonsson. “Now we can also identify antigen-specific T cells using this technology. So, we can ask, are the antigen-specific T cells in the synovial lining? Are they next to blood vessels? So, where are they, and what are their cellular neighbors?”
If CD8 granzyme K-positive T cells are the leading players in RA, then CAR-T (chimeric antigen receptor-T) cell, CAR-Treg or mRNA vaccine therapy could potentially be considered as a means to turn off or dampen the autoimmune response.
“This is a very special kind of project; it cannot be done in tiny pieces. It has to be pursued as a greater, integrated effort,” says Dr. Jonsson. “We needed a funding mechanism willing to support something truly novel, including new technologies to explore entirely new questions. The Arthritis Foundation’s willingness to invest in that novelty was essential.”
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