Exploring How Innate and Adaptative Immune System Signaling Driven by T Cells Functions in Idiopathic Inflammatory Myopathy

In a manuscript published in Frontiers in Immunology in September 2023, a team from the UPMC Division of Rheumatology and Clinical Immunology outline findings from a study that explored how key cellular interactions influence the interplay between innate and adaptive immune responses in idiopathic inflammatory myopathy.

The study’s senior author was Dana P. Ascherman, MD, professor of medicine and chief of the UPMC Division of Rheumatology and Clinical Immunology.

Study Overview: Important Findings

The team’s research study, “Antigen-driven T Cell-macrophage Interactions Mediate the Interface Between Innate and Adaptive Immunity in Histidyl-tRNA-Synthetase-induced Myositis,” was designed to investigate and characterize innate and adaptative immune system interactions in IIM, specific cell types and pathways responsible for driving these interactions, and the mechanisms by which these cells drive muscle tissue inflammation/destruction. The experiments were conducted in specialized small animal models that were developed in Dr. Ascherman’s laboratory and closely recapitulate the histidyl-tRNA-synthetase (HRS)-induced form of myositis.

The experiments conducted by Dr. Ascherman and colleagues uncovered a number of mechanistic interactions that have potentially significant translational implications for our understanding of human IIM.

The first and perhaps most important finding from the study was that T cells are essential in producing the inflammatory state in affected muscle tissue in IIM. When the team induced myositis in RAG1 knock out mice that lack T cells, they found that these mice have much less inflammation than normal (“wild type”) mice — though other proinflammatory cell types including macrophages were often seen. The importance of T cells was further demonstrated in experiments involving mice containing T cells that lacked specific innate immune signaling pathways, which reduced — but did not completely eliminate — muscle inflammation.

“Our study has conclusively shown that T cells play a critical role in the disease process of IIM,” says Dr. Ascherman. “Although this observation confirms what has long been suspected in this disease, understanding the mechanisms by which T cells operate in myositis will have significant future implications for the study of this disease and our search for more effective therapeutics.”

Another important finding emerging from this study was the role of MyD88-dependent innate immune signaling pathways in recruiting T cells and other cell types such as macrophages to inflamed muscle tissue characteristic of IIM. At the same time, however, a key role for adaptive immune responses was demonstrated by the influx of clonal populations of T cells possessing specific T cell receptor sequences.

Ultimately, the most novel aspect of this study was the use of cell-specific transcriptomic profiling and complementary computational strategies to demonstrate the importance of cross-talk between T cells and other key cell types such as macrophages and fibroblasts that collectively contribute to the tissue damage found in myositis.

“Activation of T cells influences macrophage populations and resulting disease activity in IIM,” says Dr. Ascherman. “Interestingly, we found several distinct phenotypes of macrophages that, in turn, were impacted by the presence and activity of surrounding T cells. Essentially, we have been able to show that the phenotype of the T cell directly influences the phenotype of macrophages through reciprocal interactions that ultimately determine the severity of muscle inflammation/damage in autoimmune myositis.”

As an extension of this analysis, the study examined how T cells and macrophages collectively impact the phenotype and activity of fibroblasts in IIM.

“We know that T cells and macrophages affect fibroblast activity in other autoimmune disorders, so we wanted to more fully explore the potential impact of such interactions in our model of IIM,” says Dr. Ascherman.

What Dr. Ascherman and his colleagues found was that a subpopulation of T cells (TH1 cells) overexpressing the pro-inflammatory cytokine interferon gamma contribute to the activation of both macrophages and fibroblasts.

“Interactions between T cells and macrophages also affect fibroblasts,” says Dr. Ascherman. “Signals from T cells, either directly or indirectly through macrophages, drive fibroblasts away from a pro-fibrotic (scarring) phenotype to a more inflammatory state that contributes to the disease process.”

Potential Clinical Implications of the Research

Discoveries from this work have potential implications for better understanding not only IIM, but also other autoimmune disorders that may be functioning in similar ways.  For example, identifying specific cell populations and signaling pathways in this model of HRS-induced myositis is likely to reveal more robust diagnostic markers for IIM and related autoimmune diseases. Equally important, defining key interactions between T cells and various macrophage as well as fibroblast populations in this model may lead to therapeutic targets focused on signaling pathways contributing to a variety of systemic autoimmune diseases.

“The really big picture for the field stemming from our study’s findings is the importance of understanding how interactions between innate and adaptive immune responses drive myositis and other related autoimmune disorders. As we better define the signaling pathways responsible for these interactions, we will have the opportunity to develop more selective immunotherapeutic targets,” concludes Dr. Ascherman.

Learn more about the UPMC Division of Rheumatology and Clinical Immunology and the UPMC Myositis Center led by Chester V. Oddis, MD, Rohit Aggarwal, MD, MS, and Dana Ascherman, MD.

Read the entire study using the link to the open access paper below.

Reference

Reay DP, Tabib T, Wang Y, Oriss TB, Young NA, Lafyatis RA, Jarjour WN, Clemens PR, Ascherman DP. Antigen-driven T Cell-macrophage Interactions Mediate the Interface Between Innate and Adaptive Immunity in Histidyl-tRNA-Synthetase-induced Myositis. Frontiers Immunol. 2023; 14: 1238221.