Dynamics of Immune Repertoires: Exploration and Translation

This working group will focus on TCR repertoires and diversity in health and disease, and as a function of ageing. Topics to be discussed will include: i) what is the association/relation between a given T cell trajectory of differentiation and its TCR? For example, are some TCRs more likely to become exhausted, or to lead to protective and long-lasting memory responses? ii) are some TCRs more likely to become extinct during the natural ageing process, and are these TCRs private or public?  iii) what is the connection between viral evolution and TCR repertoires? For example, is viral escape more likely to happen if the immune response is mediated by private or public TCRs?

on-site participants: Niroshana Anandasabapathy, Christopher Boughter, Rob de Boer, Tomer Hertz, Nicole La Gruta, Grant Lythe, Martin Meier-Schellersheim, Evan Newell, Ruy Ribeiro, Stefan Schattgen, Veronika Zarnitsyna

scientific program

Recent advances in both germline inference and genomic long-read sequencing of immunoglobulins (IG) have revealed extensive variability of germline variable (V), diversity (D), joining (J), and constant (C) genes between individuals, populations and species. Yet, we understand little about the origin of this diversity. Germline V, D, and J genes serve as the foundation for the establishment of a diverse B cell receptor repertoire that is critical to the  adaptive immune response. Within an individual, these genes are the substrate for the generation of diversity by V(D)J recombination and by gene conversion, and for the rapid adaptive processes mediated by somatic hypermutation (SHM) that drive affinity maturation. Until recently, the naïve repertoire generated from germline genes was seen to simply provide scaffolds on which SHM could operate to generate a successful immune response. It is now clear that IG germline variants influence the shape and content of the repertoire via effects on V(D)J recombination and amino acid changes that can directly influence Ab-antigen interactions. In addition, SHM-driven adaptation is now understood to be influenced and in some cases constrained by the germline gene set found within an individual. Thus, at the population and species level, IG genes should be expected to bear footprints of the adaptive processes that have taken place during vertebrate evolution.

This workshop will explore challenges and opportunities for IG gene discovery, in different species, by inference and by genomic sequencing. It will explore the macroevolution of the IG loci, by gene duplication and gene loss, in different lineages, whether positions critical for antigen-binding show evidence of balancing (maintains diversity) or directional (one allele is favoured) selection, and whether SHM complements or replicates germline diversity. Finally, it will discuss human therapeutic opportunities arising from non-conventional IG genes of non-human species.

on-site participants: Felix Breden, Martin Corcoran, Kenneth Hoehn, William Lees, Ailene MacPherson, Rob Miller, Mats Ohlin, Ayelet Peres, Oscar Rodriguez, Alexander Yermanos

scientific program

The Working Group will focus on primary B cell immune responses, with emphasis on the GC response.  Output goals are: a) to build testable models of how topic-related processes function; b) to define and collaboratively plan new/creative experiments or reagents to test these models; c) to create summaries of the important open or unanswered questions.

The series of topics to be discussed will be in part chosen by the suggestions of the participants. Sample topic areas include:

A. What controls the quality type of initial B cell responses?

B. What are the qualitative and quantitative aspects of cell-cell interactions at extra follicular and GC sites?

C. What is the role of FDC and other stromal cells?

D. What are the mechanisms of positive and negative selection in the GC.

E. How are signals transmitted in GCBC?

F. What are the bidirectional signals between T cells and B cells during early and maturing primary responses?

G. How are metabolic programs altered as primary B cell responses progress and how does this influence outcomes?

H. What are key gene regulatory networks that define specific cell types and stages of differentiation during the primary B cell response?

I. What controls cell fate in the GC, in terms of differentiation into MBC and PC fates.

on-site participants: Oliver Bannard, Facundo Batista, Nicole Baumgarth, Michael Cancro, Rita Carsetti, Sol Efroni, Ali Ellebedy, Jose Faro, Phil Hodgkin, Andreas Hutloff, Hans-Martin Jäck, Garnett Kelsoe, Tomohiro Kurosaki, Michael Meyer-Hermann, Thierry Mora, Oliver Pabst, Harinder Singh, Jo Spencer, David Tarlinton, Gabriel D. Victora, Hedda Wardemann, Thomas Winkler, Veronika Zarnitsyna

scientific program - closed list of participants, information upon zoom link will only be sent to this very list

Mathematical and computational models have a long-standing history in immunology, and are used to demonstrate how given rules of immune-cell interactions shape the dynamics of immunological processes – ranging from repertoire dynamics to immune cell migration. More recently, artificial intelligence (AI) and machine learning (ML) models have proven their value in "learning" immunological rules from complex datasets (e.g., for prediction of TCR-binding specificities).

This workshop will bring together experts from the fields of AI/ML and computational immunology to explore how recent advances in ML can be harnessed for mechanistic modeling in computational immunology.
We believe that a combination of these approaches could potentially be immensely powerful, for example by letting ML-derived "rules" serve as input for mechanistic models. But such synergistic combinations of ML and mechanistic modeling have remained surprisingly scarce so far.
Our workshop's aim is to change this by bringing together experts from the fields of mechanistic modeling and machine learning. Together, we will explore the ways in which ML might contribute to the field of immunological modeling. Our workshop will focus on the following key questions:

•  What kind of mechanistic models would benefit from having ML-derived input? (e.g., spatial models initialized by ML image analysis)

• How could we integrate ML models directly into mechanistic models? (e.g., modeling a T-cell repertoire where each "T cell" is represented by a small ML model that determines its specificity)

• Which recent developments from the ML are of most relevance to modelers? (e.g., using physics-inspired neural networks to solve partial differential equations)

• Which data would be required to build the next generation of ML-based computational models of the immune system?

• How can the immune system itself serve as a blueprint for next-generation ML models? (e.g., in "artificial immune systems" algorithms) 

The workshop will combine tutorials on new developments in AI/ML (such as graph neural networks and ML-based PDE solvers) and artificial immune systems with talks contributed by participants who use ML in their computational immunology research. Through reflection and discussion sessions, participants will identify important focus areas in this emerging field and map out research directions for the future.

on-site participants: Filippo Castiglione, Sol Efroni, Amir Erez, Paul R. Francois, Phil Hodgkin, Judith Mandl, Heather Melichar, Thierry Mora, Armita Noumohammad, Daniel Parisi, Jérémy Postat, Maria Rodriguez Martinez, Geir Kjetil Sandve, Kevin Thurley, Inge Wortel, Li Xue, Longzhi Yang, Christine Zarges

scientific program

In order to effectively protect against an ever-shifting array of pathogens, the immune system evolves at many different scales simultaneously. This Working Group will explore recent research and open questions at each of these levels, as well as ways in which they can inform each other. The first session, “Evolution of Immunity” will focus on the emergence and molecular basis of the ability to distinguish between self and non-self.  A second session, “Evolution of Immune Specialization” will explore the development of dedicated gene families and cell types and the role of complexity in the immune system. The third session will cover “Evolution of Symbiosis,” with an emphasis on how microbiota can complement and regulate the host immune response. Finally, we will examine the “Evolution of Immune Repertoires,” looking at the ways in which the expressed B and T cell receptor repertoires in a single individual are impacted by its specific history of exposures.

on-site participants: Yasmine Belkaid, Thomas Boehm, Pierre Boudinot, Kate Buckley, Mike Criscitiello, Anthony De Tomaso, Gerard Eberl, Sebastian Fugmann, Phil Hodgkin, Katherine Knight, Lauren McGough, Thierry Mora, Matthew Nicotra, Yuko Ota, Jonathan Rast, Jacques Robert, Irene Salinas, Oriol Sunyer, Marcos Vieira

program - overview    program - detailed program

The recognition, interaction and binding of antigen peptide epitopes by T cell receptors (TCR), the so called TCR specificity, is one of the key factors of T-cell mediated adaptive immunity. With the tremendous effort put into high throughput bulk and single cell TCR sequencing in the last years, a wealth of TCR repertoire information is now at our disposition, but rarely can it be exploited to completely understand the repertoire specificities. Despite the development of many attractive approaches and models to predict TCR specificity from the sequence, there is no conclusive solution to this missing key element, so far. During our workshop, we plan to gather the experts in TCR specificity in order to discuss and explore the existing models and methods. We propose to assemble a collection of TCR sequences with confirmed specificity (e.g. cells isolated via multimer staining) for the workshop (from publicly available databases). The collection will be subjected to the methods already used and developed by the participants during the hands-on sessions. Various methods will be run by several participants in parallel, allowing for the detection of weaknesses and problems and offering troubleshooting opportunities on the spot. The results will then be compared, problems discussed and new ideas and improvements towards a novel, state of the art method will be gathered.

on-site participants: Pieter Meysman, Thierry Mora, Morten Nielsen, Aleksandra Walczak

scientific program