TY - JOUR
T1 - Predicting lymph node output efficiency using systems biology
AU - Gong, Chang
AU - Mattila, Joshua T.
AU - Miller, Mark
AU - Flynn, Jo Anne L.
AU - Linderman, Jennifer J.
AU - Kirschner, D.
N1 - Funding Information:
This work was supported by NIH R01 HL106804 (awarded to DEK and JLF), R01 EB012579 (awarded to DEK, JLF and JJL), and R01 HL 110811 (awarded to DEK, JLF and JJL) and by a University of Michigan Rackham International Student Fellowship awarded to Chang Gong . We thank Paul Wolberg and Cory Perry for software engineering and programming contributions. We thank Henry Mirsky for early work on the choice of LN ABM lattice shape and calculation of mean free path.
PY - 2013/10/21
Y1 - 2013/10/21
N2 - Dendritic cells (DCs) capture pathogens and foreign antigen (Ag) in peripheral tissues and migrate to secondary lymphoid tissues, such as lymph nodes (LNs), where they present processed Ag as MHC-bound peptide (pMHC) to naïve T cells. Interactions between DCs and T cells result, over periods of hours, in activation, clonal expansion and differentiation of antigen-specific T cells, leading to primed cells that can now participate in immune responses. Two-photon microscopy (2PM) has been widely adopted to analyze lymphocyte dynamics and can serve as a powerful in vivo assay for cell trafficking and activation over short length and time scales. Linking biological phenomena between vastly different spatiotemporal scales can be achieved using a systems biology approach. We developed a 3D agent-based cellular model of a LN that allows for the simultaneous in silico simulation of T cell trafficking, activation and production of effector cells under different antigen (Ag) conditions. The model anatomy is based on in situ analysis of LN sections (from primates and mice) and cell dynamics based on quantitative measurements from 2PM imaging of mice. Our simulations make three important predictions. First, T cell encounters by DCs and T cell receptor (TCR) repertoire scanning are more efficient in a 3D model compared with 2D, suggesting that a 3D model is needed to analyze LN function. Second, LNs are able to produce primed CD4+T cells at the same efficiency over broad ranges of cognate frequencies (from 10-5 to 10-2). Third, reducing the time that naïve T cells are required to bind DCs before becoming activated will increase the rate at which effector cells are produced. This 3D model provides a robust platform to study how T cell trafficking and activation dynamics relate to the efficiency of T cell priming and clonal expansion. We envision that this systems biology approach will provide novel insights for guiding vaccine development and understanding immune responses to infection.
AB - Dendritic cells (DCs) capture pathogens and foreign antigen (Ag) in peripheral tissues and migrate to secondary lymphoid tissues, such as lymph nodes (LNs), where they present processed Ag as MHC-bound peptide (pMHC) to naïve T cells. Interactions between DCs and T cells result, over periods of hours, in activation, clonal expansion and differentiation of antigen-specific T cells, leading to primed cells that can now participate in immune responses. Two-photon microscopy (2PM) has been widely adopted to analyze lymphocyte dynamics and can serve as a powerful in vivo assay for cell trafficking and activation over short length and time scales. Linking biological phenomena between vastly different spatiotemporal scales can be achieved using a systems biology approach. We developed a 3D agent-based cellular model of a LN that allows for the simultaneous in silico simulation of T cell trafficking, activation and production of effector cells under different antigen (Ag) conditions. The model anatomy is based on in situ analysis of LN sections (from primates and mice) and cell dynamics based on quantitative measurements from 2PM imaging of mice. Our simulations make three important predictions. First, T cell encounters by DCs and T cell receptor (TCR) repertoire scanning are more efficient in a 3D model compared with 2D, suggesting that a 3D model is needed to analyze LN function. Second, LNs are able to produce primed CD4+T cells at the same efficiency over broad ranges of cognate frequencies (from 10-5 to 10-2). Third, reducing the time that naïve T cells are required to bind DCs before becoming activated will increase the rate at which effector cells are produced. This 3D model provides a robust platform to study how T cell trafficking and activation dynamics relate to the efficiency of T cell priming and clonal expansion. We envision that this systems biology approach will provide novel insights for guiding vaccine development and understanding immune responses to infection.
KW - 3D
KW - Agent based model
KW - Effector
KW - Priming
KW - T cells
UR - http://www.scopus.com/inward/record.url?scp=84880946832&partnerID=8YFLogxK
U2 - 10.1016/j.jtbi.2013.06.016
DO - 10.1016/j.jtbi.2013.06.016
M3 - Article
C2 - 23816876
AN - SCOPUS:84880946832
SN - 0022-5193
VL - 335
SP - 169
EP - 184
JO - Journal of Theoretical Biology
JF - Journal of Theoretical Biology
ER -