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Robust and Accurate Discrimination of Self/Non-Self Antigen Presentations by Regulatory T Cell Suppression

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ABSTRACT

The immune response by T cells usually discriminates self and non-self antigens, even though the negative selection of self-reactive T cells is imperfect and a certain fraction of T cells can respond to self-antigens. In this study, we construct a simple mathematical model of T cell populations to analyze how such self/non-self discrimination is possible. The results demonstrate that the control of the immune response by regulatory T cells enables a robust and accurate discrimination of self and non-self antigens, even when there is a significant overlap between the affinity distribution of T cells to self and non-self antigens. Here, the number of regulatory T cells in the system acts as a global variable controlling the T cell population dynamics. The present study provides a basis for the development of a quantitative theory for self and non-self discrimination in the immune system and a possible strategy for its experimental verification.

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Multicellular model of T cell response.(a) A schematic illustration of the model. Each APC presents a self or non-self antigen. T cells are associated with APC in a stochastic manner, while the dissociation rate koff depends on the combination of antigen and TCR expressed on the T cell. These T cells divide only when they are associated with APC, which is suppressed by Treg cells in the environment. Tconv and Treg cells are supplied from outside the system constantly, in a ratio of 9:1, which is based on experimental observation [10]. Simultaneously, T cells which are not attached to APCs are discarded in a constant rate. (b) The distribution of koff for Tconv cells. Two distributions of  and  of Tconv cells supplied to the system are plotted. The parameters are μTconv,self = −3, μTconv,non−self = −3.75 (i.e., ΔTconv = 0.75), and σ = 1. (c) The distribution of koff for Treg cells supplied to the system. The parameters are μTreg,self = −3.75, μTconv,non−self = −3 (i.e., ΔTreg = 0.75), and σ = 1.
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pone.0163134.g001: Multicellular model of T cell response.(a) A schematic illustration of the model. Each APC presents a self or non-self antigen. T cells are associated with APC in a stochastic manner, while the dissociation rate koff depends on the combination of antigen and TCR expressed on the T cell. These T cells divide only when they are associated with APC, which is suppressed by Treg cells in the environment. Tconv and Treg cells are supplied from outside the system constantly, in a ratio of 9:1, which is based on experimental observation [10]. Simultaneously, T cells which are not attached to APCs are discarded in a constant rate. (b) The distribution of koff for Tconv cells. Two distributions of and of Tconv cells supplied to the system are plotted. The parameters are μTconv,self = −3, μTconv,non−self = −3.75 (i.e., ΔTconv = 0.75), and σ = 1. (c) The distribution of koff for Treg cells supplied to the system. The parameters are μTreg,self = −3.75, μTconv,non−self = −3 (i.e., ΔTreg = 0.75), and σ = 1.

Mentions: Fig 1a shows a schematic representation of our model. There are N APCs in the environment (e.g., lymph node) which present a self or non-self antigen chosen from Mself or Mnon−self, self or non-self antigen repertoires respectively. Here, we assume that each APC presents a single antigen to simplify the model. This assumption can be relaxed as discussed later. Tconv and Treg cells are continually supplied to the environment from outside the system, and are randomly discarded from the environment at a constant rate. Each T cell expresses a TCR randomly chosen from KTconv repertoire for Tconv cells and KTreg repertoire for Treg cells.


Robust and Accurate Discrimination of Self/Non-Self Antigen Presentations by Regulatory T Cell Suppression
Multicellular model of T cell response.(a) A schematic illustration of the model. Each APC presents a self or non-self antigen. T cells are associated with APC in a stochastic manner, while the dissociation rate koff depends on the combination of antigen and TCR expressed on the T cell. These T cells divide only when they are associated with APC, which is suppressed by Treg cells in the environment. Tconv and Treg cells are supplied from outside the system constantly, in a ratio of 9:1, which is based on experimental observation [10]. Simultaneously, T cells which are not attached to APCs are discarded in a constant rate. (b) The distribution of koff for Tconv cells. Two distributions of  and  of Tconv cells supplied to the system are plotted. The parameters are μTconv,self = −3, μTconv,non−self = −3.75 (i.e., ΔTconv = 0.75), and σ = 1. (c) The distribution of koff for Treg cells supplied to the system. The parameters are μTreg,self = −3.75, μTconv,non−self = −3 (i.e., ΔTreg = 0.75), and σ = 1.
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pone.0163134.g001: Multicellular model of T cell response.(a) A schematic illustration of the model. Each APC presents a self or non-self antigen. T cells are associated with APC in a stochastic manner, while the dissociation rate koff depends on the combination of antigen and TCR expressed on the T cell. These T cells divide only when they are associated with APC, which is suppressed by Treg cells in the environment. Tconv and Treg cells are supplied from outside the system constantly, in a ratio of 9:1, which is based on experimental observation [10]. Simultaneously, T cells which are not attached to APCs are discarded in a constant rate. (b) The distribution of koff for Tconv cells. Two distributions of and of Tconv cells supplied to the system are plotted. The parameters are μTconv,self = −3, μTconv,non−self = −3.75 (i.e., ΔTconv = 0.75), and σ = 1. (c) The distribution of koff for Treg cells supplied to the system. The parameters are μTreg,self = −3.75, μTconv,non−self = −3 (i.e., ΔTreg = 0.75), and σ = 1.
Mentions: Fig 1a shows a schematic representation of our model. There are N APCs in the environment (e.g., lymph node) which present a self or non-self antigen chosen from Mself or Mnon−self, self or non-self antigen repertoires respectively. Here, we assume that each APC presents a single antigen to simplify the model. This assumption can be relaxed as discussed later. Tconv and Treg cells are continually supplied to the environment from outside the system, and are randomly discarded from the environment at a constant rate. Each T cell expresses a TCR randomly chosen from KTconv repertoire for Tconv cells and KTreg repertoire for Treg cells.

View Article: PubMed Central - PubMed

ABSTRACT

The immune response by T cells usually discriminates self and non-self antigens, even though the negative selection of self-reactive T cells is imperfect and a certain fraction of T cells can respond to self-antigens. In this study, we construct a simple mathematical model of T cell populations to analyze how such self/non-self discrimination is possible. The results demonstrate that the control of the immune response by regulatory T cells enables a robust and accurate discrimination of self and non-self antigens, even when there is a significant overlap between the affinity distribution of T cells to self and non-self antigens. Here, the number of regulatory T cells in the system acts as a global variable controlling the T cell population dynamics. The present study provides a basis for the development of a quantitative theory for self and non-self discrimination in the immune system and a possible strategy for its experimental verification.

No MeSH data available.


Related in: MedlinePlus