Bulletin of Mathematical Biology

, Volume 73, Issue 7, pp 1645–1665 | Cite as

A Theory of Immunodominance and Adaptive Regulation

Original Article

Abstract

Immunodominance refers to the phenomenon in which simultaneous T cell responses against multiple target epitopes organize themselves into distinct and reproducible hierarchies. In many cases, eliminating the response to the most dominant epitope allows responses to subdominant epitopes to expand more fully. The mechanism that drives immunodominance is still not well understood, although various hypotheses have been proposed. One of the more prevalent views is that immunodominance is driven by passive T cell competition for space on antigen presenting cells (APCs) or for access to specific MHC:epitope complexes on the surface of APCs. However, several experimental studies suggest that passive competition alone may not fully explain the robustness of immunodominance under physiological conditions or varying proportions of antigen-specific precursor T cells and APCs. These studies propose that a mechanism of active suppression among T cells gives rise to immunodominance.

In this work, we present the novel hypothesis that mutual suppression of simultaneous T cell responses results from the appearance of adaptive regulatory T cells (iTregs) during the course of the overall T cell expansion. We extend the mathematical model of T cell expansion proposed in Kim et al. (Bull. Math. Biol. 2009, doi:10.1007/s11538-009-9463-1) to consider multiple, concurrent T cell responses. The model is formulated as a system of independent feedback loops, in which antigen-specific T cell population produces a nonspecific feedback response. Our simulations show that the fastest response to expand gives rise to a de novo generated population of iTregs that induces a premature contraction in slower or weaker T cell responses, leading to a hierarchical expansion as observed in immunodominance. Furthermore, in some cases, removing the dominant T cell response allows previously subdominant responses to develop more fully.

Keywords

Immunodominance T cell response Adaptive regulatory T cells Delay differential equations Competition model 

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Copyright information

© Society for Mathematical Biology 2010

Authors and Affiliations

  1. 1.Department of MathematicsUniversity of UtahSalt Lake CityUSA
  2. 2.Division of Hematology, Department of MedicineStanford UniversityStanfordUSA
  3. 3.Department of Mathematics and Center for Scientific Computation and Mathematical Modeling (CSCAMM)University of MarylandCollege ParkUSA

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