Professor Axel Kallies

Sex-specific regulation of adipose tissue immune cells

Adipose tissue is an energy store and a vital endocrine organ, which plays a central role in maintaining organismal metabolism. It also contains a large number and diversity of immune cells, most notably Treg cells that are critical in maintaining adipose tissue health as we have shown (Vasanthakumar et al Nat Immunol 2015). Impairments in adipose tissue immune cells result in obesity and metabolic disease, such as type 2 diabetes. We have found striking differences in the composition of immune and stromal cells within the adipose, controlled by sex hormones (Vasanthakumar et al Nature 2020). This project aims to understand sex-specific immune cell regulation and its consequences for the development of metabolic disease.

Understanding development and function of exhausted T cells in chronic infection

Cytotoxic T cells are critical for the control of viral infections. However, T cells persistently exposed to antigen during chronic viral infections or in tumors undergo dramatic changes resulting in impaired effector function, a state known as ‘exhaustion’. Recent work by us and others identified a subset of stem-like cells, termed precursors of exhausted cells, TPEX) that maintain high proliferative potential and respond to therapeutic checkpoint inhibition (Kallies et al Nat Rev Immunol 2020, Utzschneider et al Nat Immunol 2020, Gabriel et al Immunity 2021, Tsui et al Nature 2022). This project uses chronic viral infection models examines how TPEX develop and how they can be targeted to advance therapy for chronic infections and cancer.

Understanding and improving response to checkpoint inhibitor therapy in cancer

Cytotoxic T cells are essential for tumor control and immunotherapy. However, in the tumor microenvironment they often lose their effector function and express high amounts of inhibitory receptors such as PD-1, a state known as ‘exhaustion’. Recent work by us and others identified a subset of stem-like cells, termed precursors of exhausted cells, TPEX) that maintain high proliferative potential and respond to therapeutic PD-1 checkpoint inhibition (Kallies et al Nat Rev Immunol 2020, Utzschneider et al Nat Immunol 2020, Gabriel et al Immunity 2021, Tsui et al Nature 2022). This project uses tumor models to examine how TPEX develop and how they can be targeted to improve cancer therapy.

Deciphering the development of effector regulatory T cells

After exiting the thymus, Treg cells undergo further differentiation in the periphery. During this process they acquire full suppressive capacity, including IL-10 production, and further diversify into multiple specialized Treg cell types that can enter distinct tissues as we have shown (eg Cretney Nat Immunol 2011, Vasanthakumar et al Nat Immunol 2015, Nature 2020, Neumann et al Nat Immunol 2019). Here effector Treg cells exert critical functions such as repressing tissue inflammation, mediating tissue repair and regulating metabolism. This project examines the molecular control of effector Treg cell development, diversification and function.

Understanding the differentiation and function of tissue-resident memory T cells

During an immune response, T cells develop into memory cells that protect from secondary infection. Tissue-resident memory T cells (TRM) are a subset of memory T cells, residing permanently in peripheral sites such as the lung, liver and small intestine. TRM cells have also been found in cancer where they play an important role in tumor control. Based on our discovery that TRM cell specifically express the transcriptional regulator Hobit (Mackay et al Science 2016), this project uses new tools that we developed and that enable us to specifically study the development of TRM cells and target them in conditions of infection and tumor growth.