The proper functioning of the immune system relies on T-lymphocytes to travel throughout the body and home to specialized tissues to transfer molecular information. Intimate molecular communication between cells is crucial to immune cells' maturation and activation. It has been established that lymphocyte trafficking from the blood stream and the lymphatic vessels into tissues is controlled by molecular zip-codes that identify the location where lymphocytes need to adhere. The zip-codes are precise, quantitative combinations of adhesion molecules and chemokines/chemokine receptor pairs on the lymphocyte and host tissue, such that when there is a match, the lymphocyte responds by adhering rapidly. The goal of this proposal is to develop novel computational tools to understand how lymphocytes integrate and convert molecular signals into the activation of leukocyte integrins to mediate specific adhesion under flow. The basis of these tools is the integration of signal transduction networks, either involving chemokine activation of G-proteins networks or the assembly of the SLP-76 dependent signalosome', into Adhesive Dynamics, a simulator of cell adhesion. This integrated method, called Integrated Signaling Adhesive Dynamics (ISAD) can readily predict the rate of lymphocyte firm adhesion under flow.
The aims of this proposed work are to 1) extend our modeling of lymphocyte signal transduction networks to both chemokine signaling and the signalosome; 2) to integrate these models into ISAD simulations to simulate the progressive rolling and stopping of lymphocytes on defined molecular substrates; and 3) to compare our simulations with the adhesive behavior of engineered T- lymphocytes, including Jurkat cells and T cells from knock-out mice in which SLP-76 is deleted or altered, or in which diacylglycerol kinases (DGK) have been deleted. We show preliminary results that SLP-76 defects lead to a decrease in adhesiveness, and DGK defects lead to an increase in adhesiveness. The gain of function of DGK mutants is recapitulated by simulations, confirming the validity of our modeling. We will also measure and simulate how multiple chemokine signals are integrated within a single cell to give rise to adhesion, and how knock-downs of key signaling components both in T-cells and immortalized T-cells (Jurkat cells) lead to quantitative alterations in adhesion. Our comparison between simulation and experiment, and extensive sensitivity analysis, will allow us to identify ranges of parameter values consistent with experimental observations and to elucidate the key controlling pathways in lymphocyte adhesion and homing.

Public Health Relevance

Integrated Multi-scale Adhesive Dynamics Modeling of T-lymphocyte Homing Daniel A. Hammer (PI), Gary T. Koretzky (co-PI) Relevance Human immunity requires that lymphocytes travel to specific locations within the body. The homing of lymphocyte sublines is controlled through a complex molecular zip-coding, in which surface receptors on lymphocytes bind ligands on blood vessel walls, and signals inside of lymphocytes control the trafficking patterns of lymphocytes. The goal of this proposal is to develop a computational framework for modeling the interplay between adhesion and lymphocyte signal transduction to gain a better understanding of the factors that control lymphocyte homing and hence the proper response of the immune system.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Modeling and Analysis of Biological Systems Study Section (MABS)
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Gondre-Lewis, Timothy A
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University of Pennsylvania
Biomedical Engineering
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Roy, Nathan H; MacKay, Joanna L; Robertson, Tanner F et al. (2018) Crk adaptor proteins mediate actin-dependent T cell migration and mechanosensing induced by the integrin LFA-1. Sci Signal 11:
Anderson, Nicholas R; Lee, Dooyoung; Hammer, Daniel A (2018) An Experimentally Determined State Diagram for Human CD4+ T Lymphocyte CXCR4-Stimulated Adhesion Under Shear Flow. Cell Mol Bioeng 11:91-98
Carty, Shannon A; Gohil, Mercy; Banks, Lauren B et al. (2018) The Loss of TET2 Promotes CD8+ T Cell Memory Differentiation. J Immunol 200:82-91
Buffone Jr, Alexander; Anderson, Nicholas R; Hammer, Daniel A (2018) Migration against the direction of flow is LFA-1-dependent in human hematopoietic stem and progenitor cells. J Cell Sci 131:
Sklarz, Tammarah; Guan, Peng; Gohil, Mercy et al. (2017) mTORC2 regulates multiple aspects of NKT-cell development and function. Eur J Immunol 47:516-526
MacKay, Joanna L; Hammer, Daniel A (2016) Stiff substrates enhance monocytic cell capture through E-selectin but not P-selectin. Integr Biol (Camb) 8:62-72
Dominguez, George A; Anderson, Nicholas R; Hammer, Daniel A (2015) The direction of migration of T-lymphocytes under flow depends upon which adhesion receptors are engaged. Integr Biol (Camb) 7:345-55
Vargo, Kevin B; Zaki, Ajlan Al; Warden-Rothman, Robert et al. (2015) Superparamagnetic iron oxide nanoparticle micelles stabilized by recombinant oleosin for targeted magnetic resonance imaging. Small 11:1409-13
Paszek, Matthew J; DuFort, Christopher C; Rossier, Olivier et al. (2014) The cancer glycocalyx mechanically primes integrin-mediated growth and survival. Nature 511:319-25
Dominguez, George A; Hammer, Daniel A (2014) Effect of adhesion and chemokine presentation on T-lymphocyte haptokinesis. Integr Biol (Camb) 6:862-73

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