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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

Simulated cell dynamics in the blood compartment during a primary and recall response to a hypothetical acute infection (log scale). (A) Concentration of CD4+ T cells of different subsets in the blood. (B) Concentration of CD8+ T cells of different subsets in the blood. The left parts of the graphs are identical to those of Figure 6.
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Figure 7: Simulated cell dynamics in the blood compartment during a primary and recall response to a hypothetical acute infection (log scale). (A) Concentration of CD4+ T cells of different subsets in the blood. (B) Concentration of CD8+ T cells of different subsets in the blood. The left parts of the graphs are identical to those of Figure 6.

Mentions: As above, the primary response is initiated after the first round of Ag-DC input. Blood Ag-specific T cell numbers rise as the response continues and peak at day 6 and 8. After the peak, effector and EM T cells decline while the CM cell population is maintained. On day 600, the blood concentration of CM CD4+ T cells has dropped from 0.059 to 0.023 mm−3, while the CM CD8+ T cell population remains at 0.16 mm−3. The stable maintenance of CD8+ memory and decline of CD4+ memory is in agreement with mouse LCMV infection data (53). During the recall response, because of a memory cell population generated during the primary response that can faster and more strongly respond to the same antigen, both CD4+ and CD8+ T cells in the blood exceed peak levels of their primary response, peaking at 1.07 mm−3 for CD4+ and 6.05 mm−3 for CD8+ T cells. The recall response is more than twice as large as primary response for CD8+ T cells, but only marginally increased (18%) for CD4+ T cells. Such differences in CD4+ and CD8+ recall responses have been observed in LCMV experiments as well (68). After the recall response, higher levels of CM cells are maintained as compared to following the primary response (Figure 7). After the recall response ceases, the blood concentrations of CM cells are 0.094 and 0.84 mm−3 for CD4+ and CD8+ T cells, respectively. These results indicate that the antigen-specific immune memory is reinforced after the second round of challenge, as the central memory population formed in the primary challenge gets further expanded during the second round of challenge.


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)

Simulated cell dynamics in the blood compartment during a primary and recall response to a hypothetical acute infection (log scale). (A) Concentration of CD4+ T cells of different subsets in the blood. (B) Concentration of CD8+ T cells of different subsets in the blood. The left parts of the graphs are identical to those of Figure 6.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Simulated cell dynamics in the blood compartment during a primary and recall response to a hypothetical acute infection (log scale). (A) Concentration of CD4+ T cells of different subsets in the blood. (B) Concentration of CD8+ T cells of different subsets in the blood. The left parts of the graphs are identical to those of Figure 6.
Mentions: As above, the primary response is initiated after the first round of Ag-DC input. Blood Ag-specific T cell numbers rise as the response continues and peak at day 6 and 8. After the peak, effector and EM T cells decline while the CM cell population is maintained. On day 600, the blood concentration of CM CD4+ T cells has dropped from 0.059 to 0.023 mm−3, while the CM CD8+ T cell population remains at 0.16 mm−3. The stable maintenance of CD8+ memory and decline of CD4+ memory is in agreement with mouse LCMV infection data (53). During the recall response, because of a memory cell population generated during the primary response that can faster and more strongly respond to the same antigen, both CD4+ and CD8+ T cells in the blood exceed peak levels of their primary response, peaking at 1.07 mm−3 for CD4+ and 6.05 mm−3 for CD8+ T cells. The recall response is more than twice as large as primary response for CD8+ T cells, but only marginally increased (18%) for CD4+ T cells. Such differences in CD4+ and CD8+ recall responses have been observed in LCMV experiments as well (68). After the recall response, higher levels of CM cells are maintained as compared to following the primary response (Figure 7). After the recall response ceases, the blood concentrations of CM cells are 0.094 and 0.84 mm−3 for CD4+ and CD8+ T cells, respectively. These results indicate that the antigen-specific immune memory is reinforced after the second round of challenge, as the central memory population formed in the primary challenge gets further expanded during the second round of challenge.

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