TP25: Metabolic regulation of mucosal-associated invariant T (MAIT) cell anti-viral function against hepatitis B virus infection

We will determine the effector function of human MAIT cells against HBV in detail. First, we will analyse MAIT cell effector function in a comprehensive cohort of human patients infected with HBV using single cell RNA sequencing, multi-colour spectral flow cytometry and spatial transcriptomics. Moreover, we will determine the ability of MAIT cells to limit HBV replication and to kill HBV infected cells in an in vitro co-culture approach. Finally, we will unravel the role of immunemetabolism for MAIT cell anti-viral effector function using measurement of bioenergetic parameters and flow cytometry, in order to identify novel targets to enhance MAIT cell effector function against HBV.

Dr. Dr. Katrin Böttcher

Schölzel K, Schildberg FA, Welz M, Börner C, Geiger S, Kurts C, Heikenwälder M, Knolle PA, Wohlleber D. (2014) Transfer of MHC-class-I molecules among liver sinusoidal cells facilitates hepatic immune surveillance. J Hepatol. 61:600-608. (related editorial: Carambia A, Herkel J. J Hepatol. doi: 10.1016/j.jhep.2014.06.003).

Böttcher K, Rombouts K, Saffioti F, Roccarina D, Rosselli M, Hall A, Luong T, Tsochatzis EA, Thorburn D, Pinzani M. (2018) MAIT cells are chronically activated in patients with autoimmune liver disease and promote pro-fibrogenic hepatic stellate cell activation. Hepatology. 68(1):172-186. doi: 10.1002/hep.29782.

Böttcher K, Pinzani M. (2017) Pathophysiology of liver fibrosis and the methodological barriers to the development of anti-fibrogenic agents. Adv Drug Deliv Rev. 121, 3-8. doi: 10.1016/j.addr.2017.05.016.

Deschler S, Kager J, Erber J, Fricke L, Koyumdzhieva P, Georgieva A, Lahmer T, Wiessner JR, Voit F, Schneider J, Horstmann J. Iakoubov R, Treiber M, Winter C, Ruland J, Busch DH, Knolle PA, Protzer U, Spinner CD, Schmid RM, Quante M, Böttcher K. (2021) Mucosal-associated invariant T (MAIT) cells are highly activated and functionally impaired in COVID-19 patients. Viruses. 13(2): 241. doi: 10.3390/v13020241.

Project in detail +

Due to its blood supply, the liver is exposed to antigens derived from the gastrointestinal tract, and therefore characterised by a tolerogenic immune milieu. We and others have shown that this tolerogenic intrahepatic immune milieu is paving the way for chronic hepatitis B virus (HBV) infection. Inflammation and activation of hepatic stellate cells then results in liver fibrosis and cirrhosis and further perpetuates liver damage, with a strong impact on patient morbidity and mortality. In humans, MAIT cells, innate-like T cells that generate rapid immune responses, represent up to 30% of CD3+ T cells in the liver. We have identified MAIT cells as mediators of hepatic inflammation and liver fibrosis development. Moreover, MAIT cells contribute to the control of viruses, some of which are hepatotropic. Therefore, MAIT cells are equipped with effector function that can be harnessed to generate effective immune responses against HBV infection. In preparation of this application, we conducted pilot experiments supported by TRR179, indicating that MAIT cells can directly limit HBV replication in vitro (with Protzer/Wettengel). Making use of our access to clinical samples, we however observed that MAIT cell effector function is impaired in patients with untreated chronic HBV infection. Similar to T cell dysfunction that is known to be caused by alterations in metabolic pathways, we discovered distinct regulation of MAIT cell effector function by metabolism (with Knolle). Based on these findings, we hypothesize that MAIT cells contribute to anti-viral effector function against HBV, but are functionally and metabolically impaired in chronic HBV infection. We therefore aim to investigate changes in activation and anti-viral effector function of human MAIT cells from patients with acute or chronic HBV infection. We further seek to identify metabolic alterations in MAIT cells during HBV infection and to determine the metabolic requirements of MAIT cells for effective anti-viral function against HBV. To this end, we will analyse clinical samples of our comprehensive cohort of HBV patients (with Thimme, Neumann-Haefelin/Luxenburger, Böttler), as well as intrahepatic samples (with Urban/Nkongolo, Z02, Z03) and apply imaging mass cytometry (with Z02), spatial transcriptomics (with Z03), multiparameter spectral flow cytometry, metabolic analyses (with Bengsch, Knolle) and cell co-culture approaches (with Protzer/Wettengel). Unravelling the role of metabolism for MAIT cell effector function will enable the improvement of their anti-viral effector function and facilitate the development of novel therapeutic approaches towards functional cure of chronic HBV infection.