Design, assessment, and in vivo evaluation of a computational model illustrating the role of CAV1 in CD4⁺ T-lymphocytes

Authors

Brittany D. Conroy, University of Nebraska at Omaha
Tyler A. Herek, University of Nebraska at Omaha
Timonthy D. Shew, University of Nebraska at Omaha
Matthew Latner, University of Nebraska at Omaha
Joshua J. Larson, University of Nebraska at Omaha
Laura Allen, University of Nebraska at Omaha
Paul H. Davis, University of Nebraska at OmahaFollow
Tomáš Helikar, University of Nebraska‐LincolnFollow
Christine E. Cutucache, University of Nebraska at OmahaFollow

Document Type

Article

Date of this Version

12-5-2014

Citation

Conroy BD, Herek TA, Shew TD, Latner M, Larson JJ, Allen L, Davis PH, Helikar T and Cutucache CE (2014) Design, assessment, and in vivo evaluation of a computational model illustrating the role of CAV1 in CD4+ T-lymphocytes. Front. Immunol. 5:599. doi: 10.3389/fimmu.2014.00599

Comments

Copyright © 2014 Conroy, Herek, Shew, Latner , Larson, Allen, Davis, Helikar and Cutucache. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

Abstract

Caveolin-1 (CAV1) is a vital scaffold protein heterogeneously expressed in both healthy and malignant tissue. We focus on the role of CAV1 when overexpressed in T-cell leukemia. Previously, we have shown that CAV1 is involved in cell-to-cell communication, cellular proliferation, and immune synapse formation; however, the molecular mechanisms have not been elucidated.We hypothesize that the role of CAV1 in immune synapse formation contributes to immune regulation during leukemic progression, thereby warranting studies of the role of CAV1 in CD4⁺ T-cells in relation to antigen-presenting cells. To address this need, we developed a computational model of a CD4⁺ immune effector T-cell to mimic cellular dynamics and molecular signaling under healthy and immunocompromised conditions (i.e., leukemic conditions). Using the Cell Collective computational modeling software, the CD4⁺ T-cell model was constructed and simulated under CAV1^+/+, CAV1^+/−, and CAV1^−/− conditions to produce a hypothetical immune response. This model allowed us to predict and examine the heterogeneous effects and mechanisms of CAV1 in silico. Experimental results indicate a signature of molecules involved in cellular proliferation, cell survival, and cytoskeletal rearrangement that were highly affected by CAV1 knock out. With this comprehensive model of a CD4⁺ T-cell, we then validated in vivo protein expression levels. Based on this study, we modeled a CD4⁺ T-cell, manipulated gene expression in immunocompromised versus competent settings, validated these manipulations in an in vivo murine model, and corroborated acute T-cell leukemia gene expression profiles in human beings. Moreover, we can model an immunocompetent versus an immunocompromised microenvironment to better understand how signaling is regulated in patients with leukemia.