We are interested in the in vivo roles and regulation of leukocyte b2-integrins, cell adhesion and mechanical responses in a healthy and dysfunctional immune system.
Integrin-mediated cell adhesion, migration and signalling is crucial for proper immune system function. Integrins regulate leukocyte functions such as lymphocyte recirculation, access of leukocytes into inflamed tissue, phagocytosis, immune cell signaling in both lymphoid and myeloid cells, T cell activation and effector functions. Investigations of the regulation of integrins are therefore fundamental for our understanding of immune system function in health and disease. In addition, integrins are recognized therapeutic targets in the intervention with human disease. Our group is interested in the in vivo roles and regulation of leukocyte b2-integrins in a healthy and dysfunctional immune system.
Immune cells constantly traffic around the body, looking for infection. For example, immune cells such as neutrophils and T cells need to exit the blood stream and enter tissues to perform their functions, such as killing bacteria, virus-infected cells or tumor cells. The importance of b2-integrins for immune responses is shown by the rare genetic disorders, leukocyte adhesion deficiency (LAD) type I and III, where integrin expression or function is lost. In LAD-III, integrins are normally expressed but do not function properly because an important cytoplasmic regulator of integrins, called kindlin-3, is mutated. Patients with these disorders suffer from recurrent bacterial infections because of deficient immune cell trafficking and function.
Our laboratory is interested in molecular mechanisms regulating immune cell trafficking in homeostasis and inflammation. We have created a novel mouse model to investigate the role of the integrin regulator kindlin-3 in vivo. In the mouse model the integrin/kindlin link has been disrupted. We have shown that the integrin-kindlin link is necessary for immune cell adhesion and trafficking both in homeostasis and in skin inflammation, and also for optimal T cell activation in vivo.
Another interesting integrin binding molecule is filamin, a very large cytoskeletal protein. Utilizing T cell- and neutrophil-specific filamin knockout mice, we have shown that also filamin is essential both for T cell trafficking and neutrophil responses in vivo. All in all, our research has delineated molecular mechanisms regulating immune cell trafficking and function in vivo.
Fagerholm SC. 2022. Integrins in health and diseases. New Engl J Med. 387:1519-1521.
Dendritic cells are the main antigen presenting cells in the immune system and play an important role in “kicking off” the immune response. Interestingly, our work has shown that b2-integrins play a novel role in dendritic cells; these receptors restrict dendritic cell activation, programming of the dendritic cell to a migratory phenotype and migration from tissues to lymph nodes in vivo. As a result, when integrins in dendritic cells are nonfunctional, this leads to increased T cell activation in vivo, and mice where b2-integrins are dysfunctional display increased skin inflammation in vivo. We have further investigated molecular mechanisms behind these immunoregulatory effects of integrins. Very interestingly, we have found that dendritic cells expressing dysfunctional integrins display a different epigenetic signature (increased H3K4me3 histone methylation) and also a significantly different metabolic profile than wild type cells. The transcription factor Ikaros plays a central role in this cellular reprogramming. We propose that cellular interactions with the microenvironment play more important roles in regulating immune cell programming than previously thought, through so called MECHANICAL IMMUNE MEMORY. This means that the immune cell “remembers” its mechanical interactions with the environment through epigenetic and metabolic effects, which impacts on gene expression and cell function. Loss of cell adhesion to the microenvironment may constitute a new “danger signal” that induces dendritic cell reprogramming and increased immune responses in vivo.
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Our work has shown that bone marrow-derived dendritic cells deficient in β2 integrin adhesion adopt a mature, migratory phenotype, inducing better T cell activation. Interestingly, we have shown that these cells lead to enhanced tumor rejection in mouse melanoma models (B16.OVA and B16-F10). Also targeting downstream mechanisms can have the same effect. We suggest that targeting integrin-regulated dendritic cell epigenetic or metabolic reprogramming could have a great impact on cancer immunotherapy.
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