My group performs research in computational and mathematical immunology. We use mathematical models, computer simulations and bioinformatical analyses, in order to understand the dynamics of lymphocyte repertoires in the immune system. The immune response involves cells of various types, including B, T and NK lymphocytes expressing a large diversity of receptors which recognize foreign antigens and self-molecules. The various cell types interact through a complicated network of communication, regulation and control mechanisms. This is what enables the immune system to perform the functions of danger recognition, decision, action, memory and learning. The dynamics of immune cell repertoires are, as a result, highly complex and non-linear.
My lab members develop various theoretical tools - mathematical models, computer simulations and novel bioinformatical methods - in order to analyze the dynamics of the immune system in various situations and predict the results of experimental and medical interventions.
Examples of past and current research topics include:
- Mathematical models of the dynamics of the development and maturation of T and B lymphocytes. These studies led to the discoveries of feedbacks in T cell development (papers 3, 10-13, 15-17, 20-21, in the publication list), blind homeostasis in peripheral T cell populations (18), phenotypic reflux in B cell development (34, 37), and the dynamics of transitional B cell maturation in the spleen (42, 62 and work in progress). In several studies, we have also worked out the implications of our discoveries regarding the dynamics of HIV infection (18,22).
- Mathematical models of the effects of aging on the dynamics of the development and maturation of T and B lymphocytes. In T cells (9,10), we have found that, in old mice, the proliferative capacity of thymocytes is reduced, in that each cell performs fewer divisions after the first TCR gene rearrangement checkpoint. Additionally, we found that mature recirculating CD4+ helper T cells exert negative feedback effects on the proliferation of double-positive thymocytes (16,20). Our results on B cells (34, 37 and work in progress) also point at a reduction of pro-B/pre-B proliferative capacity after passing the first rearrangement checkpoint. In addition, they suggest a possible reduction of the number or quality of survival niches for the developing B lymphocytes, as the carrying capacity of the pre-B cell compartment was found to be significantly reduced in aging. This effect may be related to the accumulation of recirculating B cells in the bone marrow with aging, as we have also found that the number of "static" (non-dividing) IgM+ B cells in the bone marrow increases with age, and thus effectively reduces even further the space available for the developing B cells.
- Models and simulations for the rearrangement of B cell and T cell antigen receptor genes, and subsequent selection, which is based on receptor-ligand interactions. The generation of T and B cell repertoires has been addressed in quite a few of our studies, leading to the discoveries of biases in gene segment selection for rearrangement (24,25,32), and to the formation of a quantitative theory of repertoire selection (26,27,36). More recent work addresses the details of the molecular processes underlying gene rearrangement (53 and work in progress) and the evolution of the Ig gene locus (66).
- Models for the development of natural killer (NK) cell repertoires, from receptor gene expression to selection of functional, non-harmful cells. We have so far been the only group which addresses this complex process with computer simulations, and have reached quite a few insights regarding the rules governing NK cell "education" (33,38,43,45,58,65 and work in progress).
- Models for NK cell development and maturation in primary and secondary lymphoid organs (work in progress).
- Computer simulations of the dynamics of T cell (54) and NK cell (67) immunological synapses.
- Computer simulation studies of the competition between B lymphocyte clones during the humoral immune response, the process of hypermutation and the creation of memory cells. Such studies have yielded many new insights, including the explanation of the phenomenon of repertoire shift (23), an identification of the parameters governing isotype switch (44), and characterizing antigen-driven selection in germinal centers by extracting information from the shape characteristics of immunoglobulin (Ig) gene lineage trees (56).
- The first study on the dynamics of the humoral immune response sparked my interest in Ig gene lineage-tree based analysis of B lymphocyte clonal dynamics during the response. This has led to the development of quite a few methods for analysis of the information thus gained (31,49,41), and branched into studies of the alterations in B cell clonal dynamics in aging (29), chronic inflammation (55), autoimmune diseases (47,50,61,63), and B cell malignancies (49,52,64 and work in progress). The methods have also been used in completely different studies, such as that on RNA editing (59).
Vision for the future:
The more we learn about lymphocyte repertoires, the more we appreciate the staggering complexity that underlies their generation, selection, and function. When I started working in this area in the beginning of 1991, molecular markers and methods for investigating lymphocyte development and behavior were just being developed, and the human genome project was in its infancy - it has just presented as a possible plan to the US congress. During the years of my work in the field of theoretical immunology, I have seen it grow from a small group of interested individuals to a rich, active and challenging research field, whose members are becoming better integrated within the general immunology community. Theoretical immunology is still growing and has not yet fulfilled its potential, however. Thus, one of my career goals - aside from research - is to continue helping integrate theoretical work within all subfields of immunology. My choices of activities in professional society boards, conference and workshop organization, review and consulting boards reflect this career goal.
The theoretical immunology community has by now internalized the lesson expressed, among other places, in my earliest reviews (1-3), that the immune system - or even any given part of it - are too complex to enable system behavior prediction out of highly simplified models. Hence the rising popularity of multi-scale modeling in this community. In my group, I plan to deepen research into the development and function of lymphocyte repertoires, and combine (in computer simulations) models that will unify the genetic, molecular, and multi-cellular aspects of lymphocyte repertoire dynamics.
One of the least-explored potential benefits of the human genome project is the emerging ability to characterize samples of lymphocyte repertoires by high-throughput sequencing. This has a huge potential for identification of subtle defects or changes in immune function, and developing between vaccines, better interventions in autoimmune diseases and malignancies, and better ways to rejuvenate the immune systems of elderly people. In spite of the potential, this area has been hardly touched so far - there are only a few papers presenting such data, and only since 2009 - because it is orders of magnitude more difficult than standard sequencing and genomic analysis. First, there is the repertoire complexity itself, which means that one cannot use "reference genes" in the analysis, and the available computational tools are of no use for theoretical immunologists; research groups must struggle to create the correct experimental controls and computational tools, as exemplified by e.g. Warren et al.'s recent paper on exhaustive T-cell repertoire sequencing (published online February 2011).
Second, analysis of B cell repertoires is even more complex than that of T cell repertoires - because of the additional diversifying processes that B cells undergo, i.e. somatic hypermutation and isotype switch. My group is one of only 5-6 groups in the world that are even trying - and, while all the other groups perform repertoire analyses based on the data generated, they all come to us for analysis of the mutations, because we have already developed methods and softwares for such analyses. Thus, a central theme in my research plans is to keep developing these methods, and collaborating with leading groups, in order to remain in the cutting edge of Ig gene research.
