Research

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 beta2-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. We are currently investigating the molecular mechanisms involved in integrin/kindlin-mediated regulation of immune cell adhesion. We are also investigating the role of other integrin regulators in immune cell trafficking and functions in vivo, using transgenic mouse models.

References

Morrison VL, MacPherson M, Savinko T, Lek HS, Prescott A, Fagerholm SC. The β2 integrin-kindlin-3 interaction is essential for T-cell homing but dispensable for T-cell activation in vivo. Blood. 2013 Aug 22;122(8):1428-36. doi: 10.1182/blood-2013-02-484998. http://www.bloodjournal.org/content/122/8/1428

Morrison VL, Uotila LM, Llort Asens M, Savinko T, Fagerholm SC. Optimal T Cell Activation and B Cell Antibody Responses In Vivo Require the Interaction between Leukocyte Function-Associated Antigen-1 and Kindlin-3. J Immunol. 2015 Jul 1;195(1):105-15. doi: 10.4049/jimmunol.1402741. http://www.jimmunol.org/content/195/1/105.full

Savinko TS, Morrison VL, Uotila LM, Wolff CH, Alenius HT, Fagerholm SC. Functional Beta2-Integrins Restrict Skin Inflammation In Vivo. J Invest Dermatol. 2015 Sep;135(9):2249-57. doi: 10.1038/jid.2015.164. http://www.jidonline.org/article/S0022-202X%2815%2939013-8/abstract

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 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. In addition, mice where beta2-integrins are dysfunctional display increased skin inflammation in vivo.

These results show that integrins play important immunoregulatory roles in vivo. We are currently investigating the molecular mechanisms involved in beta2-integrin-mediated immunomodulation, using transgenic mouse models and novel proteomic methods.

References

Morrison VL, James MJ, Grzes K, Cook P, Glass DG, Savinko T, Lek HS, Gawden-Bone C, Watts C, Millington OR, MacDonald AS, Fagerholm SC. Loss of beta2-integrin-mediated cytoskeletal linkage reprogrammes dendritic cells to a mature migratory phenotype. Nat Commun. 2014 Oct 28;5:5359. doi: 10.1038/ncomms6359. http://www.nature.com/articles/ncomms6359

Savinko TS, Morrison VL, Uotila LM, Wolff CH, Alenius HT, Fagerholm SC. Functional Beta2-Integrins Restrict Skin Inflammation In Vivo. J Invest Dermatol. 2015 Sep;135(9):2249-57. doi: 10.1038/jid.2015.164. http://www.jidonline.org/article/S0022-202X%2815%2939013-8/abstract