Making Science Fun: A tribute to our friend and colleague Antonius G. Rolink 19/04/1953-06/08/2017.
- 1Center for Chronic Immunodeficiency, University Medical Center Freiburg, Germany
- 2Nikolaus-Fiebiger-Zentrum für Molekulare Medizin, Universität Erlangen-Nürnberg, Germany
- 3Regenerative Medicine Institute, National University of Ireland Galway, Ireland
Cover image of GFP+ pro-B cells growing on stromal cells courtesy of Dr Julia Merkenschlager
Making Science Fun
A tribute to our friend and colleague
Antonius G. Rolink
Hermann Eibel1, Thomas Winkler2 and Rhodri Ceredig3
This Research Topic was organised to honour the memory of our dear friend Antonius "Ton" Rolink. The contributions are from his former students, colleagues and collaborators. In the form of original research and review articles, these papers cover many of Ton's scientific interests in different aspects of lymphocyte development in mouse and man. Thus, the majority of articles concern B cell biology, ranging from papers by Pang et al. and Kim & Schaniel on stem cells (1, 2) to Klein et al. and Winkler & Mårtensson on B cell precursors (3, 4), Brennecke et al. and Hobeika et al. on inducible B cell development (5, 6), Eibel & Smulski and Kowalczyk-Quintas et al. on B cell Activating Factor (BAFF) and B cell survival (7-9), Greaves et al. on tolerance (10) and Song & Matthias on the formation of germinal centers (11). However, Ton's research was also motivated by his continuous interest in T cells and graft-versus-host reactions, lymphoid tumours and in the application of antibody technology to develop novel therapeutic approaches. These subjects are covered by the contributions of Mori & Pieters (12) on T cells, Calvo-Asensio et al. on T cell progenitors (13), by the article of P. Ghia on leukemia development (14), by S. Heiler et al. on GvH (15) and by Hellmann et al (16) on human antibody libraries.
Word count 222 in Part 1
Ton’s scientific career
Ton Rolink began his scientific career as a PhD student in the group of Ernst Gleichman at the University of Amsterdam focussing on the mechanisms of T cell mediated immunopathology during Graft versus Host Disease (GvHD). This resulted in a remarkable output of twelve publications, including five in the Journal of Experimental Medicine (1-12).
In 1983, he moved to the Basel Institute of Immunology (BII) as a Scientific Member, joining the laboratory of Fritz Melchers. In the following years, the team developed the technologies and skills that led to the discovery of fundamental principles in B cell development (13-16), B cell tolerance (17) and autoimmunity (18-20). Over the years, Ton and his collaborators generated many monoclonal antibodies, some of which, including those to precursor B cells (21), the IL-5 receptor (22), CD40 (23), CD93 (24) and BAFF (25), resulted in numerous novel findings and publications.
One of his key technical advances was the establishment of a stroma cell-based in vitro system allowing the cultivation of B cell precursors starting with single hematopoietic stem cells (26). Since Ton indeed had “green fingers” for growing cells, he was naturally gifted at cell culture. This culminated in 1999 with two seminal articles in Nature describing how Pax5-deficient pro B cell lines could proceed along different developmental pathways to become antigen-presenting dendritic cells, osteoclasts, granulocytes or natural killer cells in vitro and to T cells following reconstitution of mice in vivo (27, 28). The discovery that the transcription factor Pax5 was a master regulator of B cell development had a profound influence on the field of haematopoiesis and lymphopoiesis and opened new research avenues allowing in depth analysis of the roles of transcriptional regulation in lymphocyte development (29-35).
By refining the conditions of in vitro B cell development, the roles of different chemokines and cytokines implicated in B cell development and homeostasis were investigated (36-40) including the detailed dissection in mouse and man of the role of the B cell Activating Factor (BAFF) (41, 42) in normal B cell homeostasis and as well as in the development of autoimmunity (43-46). Using emerging molecular technologies, Ton and his group dissected B cell development at the single cell level, analysing their genotypic and transcriptomic profiles (47-49). For this, techniques capable of identifying rearrangement of DH and JH genes on one immunoglobulin heavy chain allele, corresponding to one molecule of rearranged DNA, could be detected (50). Without a doubt, Ton’s research contributions were recognized world-wide and he became a leader in studies of mouse and human B cell development.
Having shown the multi-lineage differentiation capacity of Pax 5 KO pro-B cell lines, Ton identified a B220+CD117lowCD19- progenitor cell type with equivalent differentiation capacity for lymphocytes and myelocytes in the normal mouse bone marrow. This progenitor was referred to as an Early Progenitor with Lymphocyte and Myeloid Potential, or EPLM (51). More recent experiments using additional markers and taking advantage of single cell RNA sequencing, revealed that the original EPLM population is both phenotypically and genotypically heterogenous with the earliest member being already committed to either lymphoid or myeloid lineages (52, 53).
Seeing that mice could be reconstituted with genetically-modified B cell progenitors grown in vitro led Ton to expand his studies to T cell development (54). Realising that stromal cell-based culture systems would pose difficulties for clinical approval, he established stromal cell-free culture conditions where early mouse as well as human T cell progenitors could be expanded and differentiated with the exclusive addition of recombinant proteins and cytokines. The system was affectionately called “the plastic thymus” (55) and allowed the dissection of the signals involved in T cell commitment (56-58). In recent years, this led to to a series of experiments investigating the possible instructive role of cytokines, in particular of IL-7 and Flt3L, on lymphocyte development (52, 59-61).
This work with T cells set the foundation for his subsequent studies on T cell autoimmunity. Using T cell progenitors from genetically-modified mice, his group was able to expand and reconstitute the T cell compartment of immunodeficient recipients (62). However, the “plastic thymus” could not replace one of the key functions of the thymus, namely the generation of regulatory T cells (63). Without endogenous regulatory T cells, recipient mice reconstituted with in vitro generated T cell progenitors developed immunopathology reminiscent of that seen in GvHD. Addition of regulatory T cells to the inoculum was sufficient to prevent disease onset, providing Ton with a functional in vivo assay for regulatory T cell function.
Ton’s interest in autoimmunity associated with GvHD, initiated whilst a PhD student and continued at BII and the University of Basel, interested him until the very end of his career. In his latest publications he looked at this topic from a T-cell (64) and a B-cell perspective (65). In the first, Heiler et al. (64) analysed the contribution of the different T cell compartments at various stages of disease, the latter (65) showed the processes by which self-reactive antibodies might arise in aged mice.
Ton Rolink's key findings in the field of lymphocyte biology as well as his talent for developing numerous monoclonal antibodies and cultivation systems which are now used in many laboratories world-wide as research tools were always complemented by his open, friendly, and generous personality. Throughout his scientific career, Ton worked almost every day at the bench. He was always ready to share his ideas, tools and expertise with his colleagues and collaborators, which in times of a steadily growing number of Material Transfer Agreements (MTAs), research contracts and "highly confidential information" was a rare phenomenon in science. Therefore, Ton will not only be remembered for his exceptional work ethic and output, but also, and maybe even more, for his exceptional way of making science fun. He will also be remembered by his colleagues and collaborators by way of their projects that live and thrive through his tools and spirit.
Word count 980 words in part 2
The cartoon has been painted and kindly provided by Professor Daniela Finke, who has been for many years Ton Rolink's colleague at the Department of Biomedicine, University of Basel
Keywords: lymphocyte development and function, B cells, T cells, hemopoiesis, Graft Versus Host Desease, BAFF - B-cell activating factor, Treg cells, monoclonal antibodies
Received: 02 Nov 2018;
Accepted: 28 Nov 2018.
Edited by:Barbara L. Kee, University of Chicago, United States
Copyright: © 2018 Eibel, Winkler and Ceredig. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Rhodri Ceredig, National University of Ireland Galway, Regenerative Medicine Institute, Galway, None, Galway, Ireland, email@example.com