Utrecht Center for Quantitative Immunology
Jose A. M. Borghans
Laboratory Translational Immunology
University Medical Center Utrecht
Our major line of research encompasses the study of leukocyte dynamics. For decades immunologists have tried to estimate the typical proliferation and death rates of diverse leukocyte populations. Even though these rates are often regarded textbook immunology, estimates easily vary by more than 100-fold. Nevertheless, these turnover rates are a key factor in our understanding of many immunological processes in health and disease. Moreover, we are trying to reveal how human diseases like HIV infection, and therapeutic interventions such as haematopoietic stem-cell transplantation, affect lymphocyte kinetics, but as long as there is controversy about the lymphocyte kinetics in healthy individuals, such questions remain hard to address. Thanks to recent experimental advances, including the application of stable-isotope labelling to measure cells that undergo proliferation, the time is now ripe to determine these rates of leukocyte turnover. However, proper interpretation of the experimental data hinges upon the use of mathematical models; without such models, labelling curves remain merely descriptive and do not yield the quantitative turnover parameters that are needed.
Unfortunately, there is still a large gap between immunologists and mathematicians, which hampers a potentially fruitful synergy between the two fields of research. I have recently been awarded a VIDI-grant from the Netherlands Organization for Scientific Research (NWO) to bridge this gap, and to develop a truly interdisciplinary line of research where experiments are interpreted using mathematical models, which in turn suggest new experiments. This interdisciplinary approach is used to determine the typical rates of cell death and proliferation of different leukocyte populations in healthy subjects, to study how these rates change with age, and to study the contribution of the thymus to the maintenance of the peripheral T-cell pool. Similar studies in patients should reveal how the population dynamics of various leukocyte populations change when the immune system is disturbed by infections such as HIV, or by haematopoietic stem cell transplantation.
A second line of research addresses the role of cytotoxic T-lymphocyte responses and human leukocyte antigen (HLA) molecules in HIV-disease progression. Some HLA types have been associated with delayed HIV-disease progression, while others are clearly associated with rapid progression. We investigate two alternative hypotheses that could explain these associations. The first hypothesis is that common HLA types are no longer protective because HIV has evolved to escape presentation by these HLA molecules. The second hypothesis states that protective HLA molecules present epitopes from constrained HIV-1 regions for which escape mutations reduce the fitness of the virus. In line with the latter hypothesis, our bio-informatic analyses have pointed out that certain HLA molecules provide better protection to HIV disease progression than others because of intrinsic differences in their tendency to bind peptides from the HIV-p24 protein.
Five key publications
- Closing the gap between T-cell life span estimates from stable isotope-labeling studies in mice and humans.
Westera L, Drylewicz J, den Braber I, Mugwagwa T, van der Maas I, Kwast L, Volman T, van de Weg-Schrijver EH, Bartha I, Spierenburg G, Gaiser K, Ackermans MT, Asquith B, de Boer RJ, Tesselaar K, Borghans JA.
Blood. 2013 Sep 26;122(13):2205-12. doi: 10.1182/blood-2013-03-488411.
Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans.
den Braber I, Mugwagwa T, Vrisekoop N, Westera L, Mögling R, de Boer AB, Willems N, Schrijver EH, Spierenburg G, Gaiser K, Mul E, Otto SA, Ruiter AF, Ackermans MT, Miedema F, Borghans JA, de Boer RJ, Tesselaar K.
Immunity. 2012 Feb 24;36(2):288-97. doi: 10.1016/j.immuni.2012.02.006.
Long-term restoration of the human T-cell compartment after thymectomy during infancy: a role for thymic regeneration?
van Gent R, Schadenberg AW, Otto SA, Nievelstein RA, Sieswerda GT, Haas F, Miedema F, Tesselaar K, Jansen NJ, Borghans JA.
Blood. 2011 Jul 21;118(3):627-34. doi: 10.1182/blood-2011-03-341396.
Sparse production but preferential incorporation of recently produced naive T cells in the human peripheral pool.
Vrisekoop N, den Braber I, de Boer AB, Ruiter AF, Ackermans MT, van der Crabben SN, Schrijver EH, Spierenburg G, Sauerwein HP, Hazenberg MD, de Boer RJ, Miedema F, Borghans JA, Tesselaar K.
Proc Natl Acad Sci U S A. 2008 Apr 22;105(16):6115-20. doi: 10.1073/pnas.0709713105.
Quantification of T-cell dynamics: from telomeres to DNA labeling.
Borghans JA, de Boer RJ.
Immunol Rev. 2007 Apr;216:35-47.
and in TBB