TY - JOUR
T1 - In silico investigation into dendritic cell regulation of CD8Treg mediated killing of Th1 cells in murine experimental autoimmune encephalomyelitis
AU - Williams, Richard A.
AU - Greaves, Richard
AU - Read, Mark
AU - Timmis, Jon
AU - Andrews, Paul S.
AU - Kumar, Vipin
N1 - Funding Information:
This paper represents a major extension of an abstract [22] that was presented at the 10th International Conference on Artificial Immune Systems (ICARIS 2011), held in Cambridge, July 2011. Paul S Andrews was supported by EPSRC grant number EP/E053505/1 and now EPSRC grant number EP/ I005943/1. Mark Read and Jon Timmis are supported by the EC funded CoCoRo Project, GA 270382 [http://cocoro.uni-graz.at/drupal/]. Richard A Williams, Jon Timmis and Mark Read also acknowledge financial support from EP/E053505/1 and the Non-Standard Computation Group, University of York. Jon Timmis would also like to acknowledge support from the Royal Society. VK is supported by grants from the National Institutes of Health, USA and from the Multiple Sclerosis National Research Institute.
PY - 2013/4/17
Y1 - 2013/4/17
N2 - Background: Experimental autoimmune encephalomyelitis has been used extensively as an animal model of T cell mediated autoimmunity. A down-regulatory pathway through which encephalitogenic CD4Th1 cells are killed by CD8 regulatory T cells (Treg) has recently been proposed. With the CD8Treg cells being primed by dendritic cells, regulation of recovery may be occuring around these antigen presenting cells. CD4Treg cells provide critical help within this process, by licensing dendritic cells to prime CD8Treg cells, however the spatial and temporal aspects of this help in the CTL response is currently unclear.Results: We have previously developed a simulator of experimental autoimmune encephalomyelitis (ARTIMMUS). We use ARTIMMUS to perform novel in silico experimentation regarding the priming of CD8Treg cells by dendritic cells, and the resulting CD8Treg mediated killing of encephalitogenic CD4Th1 cells. Simulations using dendritic cells that present antigenic peptides in a mutually exclusive manner (either MBP or TCR-derived, but not both) suggest that there is no significant reliance on dendritic cells that can prime both encephalitogenic CD4Th1 and Treg cells. Further, in silico experimentation suggests that dynamics of CD8Treg priming are significantly influenced through their spatial competition with CD4Treg cells and through the timing of Qa-1 expression by dendritic cells.Conclusion: There is no requirement for the encephalitogenic CD4Th1 cells and cytotoxic CD8Treg cells to be primed by the same dendritic cells. We conjecture that no significant portion of CD4Th1 regulation by Qa-1 restricted CD8Treg cells occurs around individual dendritic cells, and as such, that CD8Treg mediated killing of CD4Th1 cells occurring around dendritic cells is not critical for recovery from the murine autoimmune disease. Furthermore, the timing of the CD4Treg licensing of dendritic cells and the spatial competition between CD4Treg and CD8Treg cells around the dendritic cell is critical for the size of the cytotoxic T lymphocyte response, because dendritic cells have a limited lifespan. If treatments can be found to either speed up the licensing process, or increase the spatial competitiveness of CD8Treg cells, the magnitude of the cytotoxic T lymphocyte response can be increased.
AB - Background: Experimental autoimmune encephalomyelitis has been used extensively as an animal model of T cell mediated autoimmunity. A down-regulatory pathway through which encephalitogenic CD4Th1 cells are killed by CD8 regulatory T cells (Treg) has recently been proposed. With the CD8Treg cells being primed by dendritic cells, regulation of recovery may be occuring around these antigen presenting cells. CD4Treg cells provide critical help within this process, by licensing dendritic cells to prime CD8Treg cells, however the spatial and temporal aspects of this help in the CTL response is currently unclear.Results: We have previously developed a simulator of experimental autoimmune encephalomyelitis (ARTIMMUS). We use ARTIMMUS to perform novel in silico experimentation regarding the priming of CD8Treg cells by dendritic cells, and the resulting CD8Treg mediated killing of encephalitogenic CD4Th1 cells. Simulations using dendritic cells that present antigenic peptides in a mutually exclusive manner (either MBP or TCR-derived, but not both) suggest that there is no significant reliance on dendritic cells that can prime both encephalitogenic CD4Th1 and Treg cells. Further, in silico experimentation suggests that dynamics of CD8Treg priming are significantly influenced through their spatial competition with CD4Treg cells and through the timing of Qa-1 expression by dendritic cells.Conclusion: There is no requirement for the encephalitogenic CD4Th1 cells and cytotoxic CD8Treg cells to be primed by the same dendritic cells. We conjecture that no significant portion of CD4Th1 regulation by Qa-1 restricted CD8Treg cells occurs around individual dendritic cells, and as such, that CD8Treg mediated killing of CD4Th1 cells occurring around dendritic cells is not critical for recovery from the murine autoimmune disease. Furthermore, the timing of the CD4Treg licensing of dendritic cells and the spatial competition between CD4Treg and CD8Treg cells around the dendritic cell is critical for the size of the cytotoxic T lymphocyte response, because dendritic cells have a limited lifespan. If treatments can be found to either speed up the licensing process, or increase the spatial competitiveness of CD8Treg cells, the magnitude of the cytotoxic T lymphocyte response can be increased.
KW - Animals
KW - Antigen-Presenting Cells/immunology
KW - Autoimmune Diseases/complications
KW - CD8-Positive T-Lymphocytes/immunology
KW - Computer Simulation
KW - Dendritic Cells/immunology
KW - Encephalomyelitis, Autoimmune, Experimental/immunology
KW - Histocompatibility Antigens Class I/immunology
KW - Humans
KW - Mice
KW - T-Lymphocytes, Cytotoxic/immunology
KW - T-Lymphocytes, Regulatory/immunology
KW - Th1 Cells/immunology
UR - http://www.scopus.com/inward/record.url?scp=84877921262&partnerID=8YFLogxK
U2 - 10.1186/1471-2105-14-S6-S9
DO - 10.1186/1471-2105-14-S6-S9
M3 - Article
C2 - 23734666
AN - SCOPUS:84877921262
SN - 1471-2105
VL - 14
JO - BMC Bioinformatics
JF - BMC Bioinformatics
IS - SUPPL6
M1 - S9
ER -