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	Rob J. de Boer
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Theoretical Immunology

Theoretical immunology is maturing into a discipline where modeling and bioinformatics helps to interpret experimental data to allow for more quantitative interpretations, to predict epitopes, to resolve controversies, and to suggest novel experiments allowing for more conclusive insights. My theoretical immunology group in Utrecht works in the following major areas:

• Quantify the population dynamics of lymphocytes by estimating the normal turnover rates of naive and memory T cells, and the killing rates of cytotoxic cells, by fitting mathematical models to experimental data. With: José Borghans.
• Study host-pathogen evolution by bioinformatics and by in silico evolution. With MHC peptide prediction tools we study the overlaps between self and non-self, which peptides from a pathogen are most immunogenic in which host, and why some MHC are more protective than others. With: Can Kesmir.
• Quantify immune responses to viruses. We fit mathematical models to data on the CD8 immune response to viruses, model immune escape, and compare acute with chronic immune reactions.
• Study the migration of cells as revealed by multi-photon microscopy to characterize the motility of cells, their contact times, and the in vivo killing rates of cytotoxic T cells. With: Joost Beltman and Stan Marée.
• Study helper T cell phenotype differentiation by modeling master regulators like Tbet and Gata3, and analyzing cytokine expression data.

With the modeling approach we study the population dynamics within the immune system. We aim to understand how the system maintains its diversity of millions of lymphocyte populations, and to understand how their population densities are maintained by possible homeostatic mechanisms. HIV infection is an important focus area because we aim to understand how this virus perturbs the normal population dynamics, leading to CD4 T cell depletion. We have used T cell receptor excision circles (TRECs) to quantify the number of naive T cells and their division rates. Labeling techniques that we focus on are BrdU, deuterium, and CFSE.

Our bioinformatic approach suggests that different MHC molecules target different proteins from the same pathogen and therefore differ in the degree of immune protection (e.g., p24 and B57 and B27 in HIV infection). We have used pMHC prediction tools to study the evolution of HIV-1 to its new human host, and have explained how the monomorphic parts of the antigen processing pathway (like TAP and proteasome) are protected from pathogen escape by the more specific and polymorphic MHC.

With the cellular Potts model (CPM) we have been able to produce in silico movies of T cell migration that look so realistic that we used them as an artificial environment to measure parameters of T cell behavior that can hardly be measured in vivo.

Ten recent key publications

Schmid B., Kesmir C. & De Boer R.J. (2008).
The specificity and polymorphism of the MHC class I prevents the global adaptation of HIV-1 to the monomorphic proteasome and TAP.
PLoS. ONE., 3: e3525. DOI. DownLoad PDF. MEDLINE.

Van den Ham H.J. & De Boer R.J. (2008).
From the two-dimensional Th1 and Th2 phenotypes to high-dimensional models for gene regulation.
Int. Immunol., 20: 1269-1277. DOI. DownLoad PDF. MEDLINE.

Borghans J.A., Mølgaard A., De Boer R.J. & Kesmir C. (2007).
HLA alleles associated with slow progression to AIDS truly prefer to present HIV-1 p24.
PLoS ONE, 2: e920. DOI. DownLoad PDF. MEDLINE.

Ganusov V.V., Milutinovic D. & De Boer R.J. (2007).
IL-2 regulates expansion of CD4 T cell populations by affecting cell death: insights from modeling CFSE data.
J. Immunol., 179: 950-957. MEDLINE.

Ganusov V.V. & De Boer R.J. (2007).
Do most lymphocytes in humans really reside in the gut?
Trends Immunol., 28: 514-518. DOI. DownLoad PDF. MEDLINE.

Althaus C.L., Ganusov V.V. & De Boer R.J. (2007).
Dynamics of CD8 T Cell Responses during Acute and Chronic Lymphocytic Choriomeningitis Virus Infection.
J. Immunol., 179: 2944-2951. DownLoad PDF. MEDLINE.

Beltman J.B., Marée A.F., Lynch J.N., Miller M.J. & De Boer R.J. ( 2007).
Lymph node topology dictates T cell migration behavior.
J. Exp. Med., 204: 771-780. DownLoad PDF. MEDLINE.

De Boer R.J. (2007).
Understanding the failure of CD8 T-cell vaccination against simian/human immunodeficiency virus.
J. Virol., 81: 2838-2848. DOI. DownLoad PDF. MEDLINE.

Hazenberg M.D., Otto S.A., Van Rossum A.M., Scherpbier H.J., De Groot R., Kuijpers T.W., Lange J.M., Hamann D., De Boer R.J., Borghans J.A. & Miedema F. (2004).
Establishment of the CD4 T-cell pool in healthy children and untreated children infected with HIV-1.
Blood, 104: 3513-3519. DownLoad PDF. MEDLINE.

Burroughs N.J., De Boer R.J. & Kesmir C. (2004).
Discriminating self from nonself with short peptides from large proteomes.
Immunogenetics., 56: 311-320. DownLoad PDF. MEDLINE.