Systems Immunology

Group Leader: Roger Geiger
Researchers:Gaia Antonini, Fernando Canale, Yun Ding, Wenjie Jin, Ian Vogel, Giada Zoppi

T cells are key players in the immune system with the ability to detect and eliminate infected cells and tumors. We study molecular regulations underlying T cell activation and anti-tumor activity. For this, we use a wide range of technologies including mass spectrometry-based proteomics, functional genomics, and microfluidics-based systems. Our projects aim to provide detailed insights into T cell functionality that can be translated into the clinic to improve anti-cancer immunotherapies.

We are particularly interested in the immune response to liver cancer. T cells that infiltrate liver tumors are often exhausted and do not work properly. To potentially increase their functionality, we study the underlying regulations by systematically analyzing tumor-infiltrating T cells with high-resolution mass spectrometry and functional assays.

In a related project, we develop workflows to efficiently isolate T cells that recognize liver tumor antigens. Tumor-reactive T cells can be grown to large numbers and used for adoptive T cell therapies, a highly personalized form of cancer therapy. In collaboration with the research group of Andrew deMello (ETH Zürich), we use droplet-based microfluidics systems to manipulate and analyze single T cells in a high-throughput format.

For more information, please visit https://www.geigerlab.org/

Projects

Project 1

Group leaders: Mariagrazia Uguccioni
Researchers: Gianluca D’Agostino – PhD Student, Gabriela Danelon Sargenti -Technician
Status: In progress

Chemokines have emerged as key controllers of integrin function and cell locomotion. A vast range of in situ experiments has revealed that a variety of chemokines can be concomitantly produced in physiology, as well as in tumours. This renders the chemokine system a good target for therapy, and has increased the search, by pharmaceutical companies, for chemokine antagonists. While we understand well the effects of different chemokines one by one, much less was known about the potential consequences of the expression of multiple chemokines, cytokines, toll like receptor ligands or different inflammatory molecules, on cell responses to chemokines. Chemokine structure/function studies led us to identify chemokines that can act as natural antagonists by preventing natural agonist binding and the subsequent activation of the receptor. Recently, we have described chemokines that can act in synergism with chemokine receptor agonists, forming heterocomplexes able to induce functional responses at lower agonist concentration. There is no more doubt that the synergism between chemokines is crucial at the very early stage of inflammation, while the study of the role of molecules, such as the alarmin High Mobility Group Box 1 (HMGB1), that can synergise with chemokines is at its infancy.

Project 2

Group leaders: Mariagrazia Uguccioni
Researchers: Gabriela Danelon Sargenti – Technician
Status: In progress

We have recently provided evidence that HMGB1, a damage associated molecular pattern protein (DAMP), can synergise with the CXCR4 agonist, CXCL12, promoting immune cell influx in injured tissues and enhancing immune cell responses. Cell income is blocked by glycyrrhizin, the sweet tasting compound of liquorice root, able to abolish the synergistic effect of HMGB1 on CXCL12-dependent migration, without affecting CXCL12/CXCR4 interaction. Given the fact that CXCL12 is strongly expressed in many tissues, favouring cell influx and egression, we aim to characterize in vitro and in vivo the mechanisms of action of chemokine synergy-inducing molecules on cell trafficking.

These studies might pave the way to establish novel approaches for controlling leukocyte migration and activities.

Project 3

Group leaders: Mariagrazia Uguccioni
Researchers: Valentina Cecchinato – Scientist, Gabriela Danelon Sargenti – Technician
Status: In progress

30 years after the discovery of human immunodeficiency virus (HIV) as the causative agent of AIDS, the mechanisms governing pathogenesis and disease progression are still not fully understood. Indeed, a progressive impairment of the immune system, with alterations that affect both innate and adaptive immunity, characterizes the infection with HIV‑1 in humans and with simian immunodeficiency virus (SIV) in macaques. It has been proposed that a state of chronic immune activation contributes to the loss of CD4⁺ T cells and to alterations of immune responses, ultimately leading to disease progression.

The loss of CD4⁺CCR5⁺ T cells in the gut associated lymphoid tissue (GALT) has been well documented both in the natural host and in pathogenic models of SIV infection. A decrease in the frequency of Th17 cells, a subset of effector T cells involved in the immune response against extracellular bacteria, has been described by Dr. Cecchinato in the mucosa of SIV infected animals. Nevertheless, the migratory capacity of this T cell subpopulation has not been investigated so far.

Chemokines are important mediators of leukocyte trafficking and function, and deregulation of their expression might contribute in part to the pathogenesis of HIV-1/SIV infection. In the frame of a projects funded by the European Community and by the Swiss HIV Cohort Study, we are investigating the mechanisms that mediate CCR6⁺/Th17 cells trafficking and activities at mucosal sites together with their decrease in frequency during HIV/SIV infection in order to better understand the pathogenesis of AIDS and in view of generating efficient vaccines.

Systems Immunology

Institute for Research in Biomedicine

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