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

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.

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Response of T cell populations with respect to antigen presentation.(a) The average number of Tconv cells as a function of the fraction of the target antigen rt. Each dot represents the result obtained by presentation of different randomly chosen target antigen. The average number of Tconv cells is obtained by averaging the number over 1000 time units after the system settled down to a steady state. (b) The distribution of koff of Tconv cells to the non-self target antigens. The distribution is obtained after the system falls into a steady state. When rt is small (≲ 0.1), the distribution of koff is almost identical to that of supplied Tconv cells to the environment (the distribution is shown in Fig 1b). In contrast, in the region of rt ≳ 0.1, the dissociation rate to the target antigen significantly decreases, indicating that T cells having high affinity to the target are selectively amplified. (c) The average number of Treg cells as a function of the fraction of the target antigen rt. Each dot represents the result obtained by presentation of a different target antigen. The parameters used in these calculations are N = 1000, Mself = Mnon−self = 5000, KTconv = KTreg = 5000, kon = 0.1, α = 30, and β = 10. Tconv and Treg cells with randomly chosen TCRs are continuously supplied to the environment at a ratio of 9:1. The flow rate of T cell supply to the environment is 0.5 cell per unit time, while cells which are not attached to an APC are randomly discarded from the environment with a probability of 0.05 per unit time.
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pone.0163134.g002: Response of T cell populations with respect to antigen presentation.(a) The average number of Tconv cells as a function of the fraction of the target antigen rt. Each dot represents the result obtained by presentation of different randomly chosen target antigen. The average number of Tconv cells is obtained by averaging the number over 1000 time units after the system settled down to a steady state. (b) The distribution of koff of Tconv cells to the non-self target antigens. The distribution is obtained after the system falls into a steady state. When rt is small (≲ 0.1), the distribution of koff is almost identical to that of supplied Tconv cells to the environment (the distribution is shown in Fig 1b). In contrast, in the region of rt ≳ 0.1, the dissociation rate to the target antigen significantly decreases, indicating that T cells having high affinity to the target are selectively amplified. (c) The average number of Treg cells as a function of the fraction of the target antigen rt. Each dot represents the result obtained by presentation of a different target antigen. The parameters used in these calculations are N = 1000, Mself = Mnon−self = 5000, KTconv = KTreg = 5000, kon = 0.1, α = 30, and β = 10. Tconv and Treg cells with randomly chosen TCRs are continuously supplied to the environment at a ratio of 9:1. The flow rate of T cell supply to the environment is 0.5 cell per unit time, while cells which are not attached to an APC are randomly discarded from the environment with a probability of 0.05 per unit time.

Mentions: To investigate the mechanism of self/non-self discrimination, we consider the case that one randomly chosen self or non-self target antigen is presented on a certain fraction of APCs, while the other APCs present various self antigens selected randomly. Fig 2a shows the average number of Tconv cells in the system as a function of the fraction of the target antigen denoted by rt. The number of Tconv cells was obtained after the system falls into a steady state of the cell number. In the case of non-self antigen presentation, the number of Tconv cells sharply increases by increasing rt. In contrast, the number of cells is almost unchanged when self target antigen is presented. In the former case, the actively dividing Tconv cells have significantly lower koff (higher affinity) for the presented target antigen than Tconv cells supplied from outside the system. Fig 2b shows how the distribution of koff of Tconv for the non-self target antigens changes by increasing rt. As shown, koff of Tconv cells significantly decreases when rt exceed a threshold level (∼0.1). In this region, Tconv cells which have higher affinities to the target antigen are selectively amplified. The resulting population is dominated by Tconv cells which are the offspring of a few such Tconv cells. The threshold level is determined by a balance between the basal reproduction activity α and the suppression of reproduction by Treg cells. We confirmed that such amplification of reactive T cells to the non-self target and tolerance to the self target are independent of the choice of self and non-self target antigens.


Robust and Accurate Discrimination of Self/Non-Self Antigen Presentations by Regulatory T Cell Suppression
Response of T cell populations with respect to antigen presentation.(a) The average number of Tconv cells as a function of the fraction of the target antigen rt. Each dot represents the result obtained by presentation of different randomly chosen target antigen. The average number of Tconv cells is obtained by averaging the number over 1000 time units after the system settled down to a steady state. (b) The distribution of koff of Tconv cells to the non-self target antigens. The distribution is obtained after the system falls into a steady state. When rt is small (≲ 0.1), the distribution of koff is almost identical to that of supplied Tconv cells to the environment (the distribution is shown in Fig 1b). In contrast, in the region of rt ≳ 0.1, the dissociation rate to the target antigen significantly decreases, indicating that T cells having high affinity to the target are selectively amplified. (c) The average number of Treg cells as a function of the fraction of the target antigen rt. Each dot represents the result obtained by presentation of a different target antigen. The parameters used in these calculations are N = 1000, Mself = Mnon−self = 5000, KTconv = KTreg = 5000, kon = 0.1, α = 30, and β = 10. Tconv and Treg cells with randomly chosen TCRs are continuously supplied to the environment at a ratio of 9:1. The flow rate of T cell supply to the environment is 0.5 cell per unit time, while cells which are not attached to an APC are randomly discarded from the environment with a probability of 0.05 per unit time.
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pone.0163134.g002: Response of T cell populations with respect to antigen presentation.(a) The average number of Tconv cells as a function of the fraction of the target antigen rt. Each dot represents the result obtained by presentation of different randomly chosen target antigen. The average number of Tconv cells is obtained by averaging the number over 1000 time units after the system settled down to a steady state. (b) The distribution of koff of Tconv cells to the non-self target antigens. The distribution is obtained after the system falls into a steady state. When rt is small (≲ 0.1), the distribution of koff is almost identical to that of supplied Tconv cells to the environment (the distribution is shown in Fig 1b). In contrast, in the region of rt ≳ 0.1, the dissociation rate to the target antigen significantly decreases, indicating that T cells having high affinity to the target are selectively amplified. (c) The average number of Treg cells as a function of the fraction of the target antigen rt. Each dot represents the result obtained by presentation of a different target antigen. The parameters used in these calculations are N = 1000, Mself = Mnon−self = 5000, KTconv = KTreg = 5000, kon = 0.1, α = 30, and β = 10. Tconv and Treg cells with randomly chosen TCRs are continuously supplied to the environment at a ratio of 9:1. The flow rate of T cell supply to the environment is 0.5 cell per unit time, while cells which are not attached to an APC are randomly discarded from the environment with a probability of 0.05 per unit time.
Mentions: To investigate the mechanism of self/non-self discrimination, we consider the case that one randomly chosen self or non-self target antigen is presented on a certain fraction of APCs, while the other APCs present various self antigens selected randomly. Fig 2a shows the average number of Tconv cells in the system as a function of the fraction of the target antigen denoted by rt. The number of Tconv cells was obtained after the system falls into a steady state of the cell number. In the case of non-self antigen presentation, the number of Tconv cells sharply increases by increasing rt. In contrast, the number of cells is almost unchanged when self target antigen is presented. In the former case, the actively dividing Tconv cells have significantly lower koff (higher affinity) for the presented target antigen than Tconv cells supplied from outside the system. Fig 2b shows how the distribution of koff of Tconv for the non-self target antigens changes by increasing rt. As shown, koff of Tconv cells significantly decreases when rt exceed a threshold level (∼0.1). In this region, Tconv cells which have higher affinities to the target antigen are selectively amplified. The resulting population is dominated by Tconv cells which are the offspring of a few such Tconv cells. The threshold level is determined by a balance between the basal reproduction activity α and the suppression of reproduction by Treg cells. We confirmed that such amplification of reactive T cells to the non-self target and tolerance to the self target are independent of the choice of self and non-self target antigens.

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