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Harnessing the heterogeneity of T cell differentiation fate to fine-tune generation of effector and memory T cells.

Gong C, Linderman JJ, Kirschner D - Front Immunol (2014)

Bottom Line: Using this model, we simulate a hypothetical immune response and reproduce both primary and recall responses to infection.Increased numbers of antigen-bearing dendritic cells (DCs) are predicted to raise production of both effector and memory T cells, and distinct "sweet spots" of peptide-MHC levels on those DCs exist that favor CD4+ or CD8+ T cell differentiation toward either effector or memory cell phenotypes.This has important implications for vaccine development and immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan , Ann Arbor, MI , USA.

ABSTRACT
Recent studies show that naïve T cells bearing identical T cell receptors experience heterogeneous differentiation and clonal expansion processes. The factors controlling this outcome are not well characterized, and their contributions to immune cell dynamics are similarly poorly understood. In this study, we develop a computational model to elaborate mechanisms occurring within and between two important physiological compartments, lymph nodes and blood, to determine how immune cell dynamics are controlled. Our multi-organ (multi-compartment) model integrates cellular and tissue level events and allows us to examine the heterogeneous differentiation of individual precursor cognate naïve T cells to generate both effector and memory T lymphocytes. Using this model, we simulate a hypothetical immune response and reproduce both primary and recall responses to infection. Increased numbers of antigen-bearing dendritic cells (DCs) are predicted to raise production of both effector and memory T cells, and distinct "sweet spots" of peptide-MHC levels on those DCs exist that favor CD4+ or CD8+ T cell differentiation toward either effector or memory cell phenotypes. This has important implications for vaccine development and immunotherapy.

No MeSH data available.


Related in: MedlinePlus

Primary response dynamics of immune cells in LN and blood during a hypothetical acute infection (log scale). (A–C) Number of dendritic cells, CD4+ and CD8+ T cells of different subsets in the LN compartment. (D,E) Concentration of CD4+ and CD8+ T cells of different subsets in the blood compartment. (A) Model input of DCs representing a hypothetical acute infection, such as LCMV and (B–E) output.
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Figure 6: Primary response dynamics of immune cells in LN and blood during a hypothetical acute infection (log scale). (A–C) Number of dendritic cells, CD4+ and CD8+ T cells of different subsets in the LN compartment. (D,E) Concentration of CD4+ and CD8+ T cells of different subsets in the blood compartment. (A) Model input of DCs representing a hypothetical acute infection, such as LCMV and (B–E) output.

Mentions: We simulated immune responses to a hypothetical acute infection by introducing Ag-DCs into the LN compartment to activate cognate T cells as shown in Figure 6A. The cognate frequency is set to 10−4. Figures 6B–E show simulated immune cell dynamics in the LN and blood compartments.


Harnessing the heterogeneity of T cell differentiation fate to fine-tune generation of effector and memory T cells.

Gong C, Linderman JJ, Kirschner D - Front Immunol (2014)

Primary response dynamics of immune cells in LN and blood during a hypothetical acute infection (log scale). (A–C) Number of dendritic cells, CD4+ and CD8+ T cells of different subsets in the LN compartment. (D,E) Concentration of CD4+ and CD8+ T cells of different subsets in the blood compartment. (A) Model input of DCs representing a hypothetical acute infection, such as LCMV and (B–E) output.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928592&req=5

Figure 6: Primary response dynamics of immune cells in LN and blood during a hypothetical acute infection (log scale). (A–C) Number of dendritic cells, CD4+ and CD8+ T cells of different subsets in the LN compartment. (D,E) Concentration of CD4+ and CD8+ T cells of different subsets in the blood compartment. (A) Model input of DCs representing a hypothetical acute infection, such as LCMV and (B–E) output.
Mentions: We simulated immune responses to a hypothetical acute infection by introducing Ag-DCs into the LN compartment to activate cognate T cells as shown in Figure 6A. The cognate frequency is set to 10−4. Figures 6B–E show simulated immune cell dynamics in the LN and blood compartments.

Bottom Line: Using this model, we simulate a hypothetical immune response and reproduce both primary and recall responses to infection.Increased numbers of antigen-bearing dendritic cells (DCs) are predicted to raise production of both effector and memory T cells, and distinct "sweet spots" of peptide-MHC levels on those DCs exist that favor CD4+ or CD8+ T cell differentiation toward either effector or memory cell phenotypes.This has important implications for vaccine development and immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan , Ann Arbor, MI , USA.

ABSTRACT
Recent studies show that naïve T cells bearing identical T cell receptors experience heterogeneous differentiation and clonal expansion processes. The factors controlling this outcome are not well characterized, and their contributions to immune cell dynamics are similarly poorly understood. In this study, we develop a computational model to elaborate mechanisms occurring within and between two important physiological compartments, lymph nodes and blood, to determine how immune cell dynamics are controlled. Our multi-organ (multi-compartment) model integrates cellular and tissue level events and allows us to examine the heterogeneous differentiation of individual precursor cognate naïve T cells to generate both effector and memory T lymphocytes. Using this model, we simulate a hypothetical immune response and reproduce both primary and recall responses to infection. Increased numbers of antigen-bearing dendritic cells (DCs) are predicted to raise production of both effector and memory T cells, and distinct "sweet spots" of peptide-MHC levels on those DCs exist that favor CD4+ or CD8+ T cell differentiation toward either effector or memory cell phenotypes. This has important implications for vaccine development and immunotherapy.

No MeSH data available.


Related in: MedlinePlus