Limits...
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.

No MeSH data available.


Self/non-self discrimination accuracy.(a) The discrimination score S as a function of basal reproduction activity α. (b) The average number of Tconv cells in the case without Treg regulation. The reproduction activity α is set to 0.1 at which the discrimination score becomes maximum. The parameters are set to those used in Fig 2, except for α.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5036821&req=5

pone.0163134.g003: Self/non-self discrimination accuracy.(a) The discrimination score S as a function of basal reproduction activity α. (b) The average number of Tconv cells in the case without Treg regulation. The reproduction activity α is set to 0.1 at which the discrimination score becomes maximum. The parameters are set to those used in Fig 2, except for α.

Mentions: It should be stressed that, without the regulation of cell proliferation by Treg cells, the clear self/non-self discrimination such as in Fig 2 is difficult when the negative selection is imperfect. To demonstrate this, we simulated the response to self or non-self antigen presentations when there are no Treg cells and where the affinity distribution of Tconv is identical to that in Fig 1b (ΔTconv = 0.75 and σ = 1). To evaluate the accuracy of self/non-self discrimination, we define the discrimination score as follows:S≡∫012{⟨Nns(rt)⟩-⟨Ns(rt)⟩}drt.(2)Here, 〈Ns(rt)〉 and 〈Nns(rt)〉 represent the average numbers of Tconv cells when a self or a non-self target antigen is presented in the ratio rt, respectively, where the average is taken over various target antigens. This discrimination score corresponds to the area between the curves of self and non-self antigen presentations in Fig 2a, which takes a larger value when the system can discriminate self and non-self antigens accurately. Fig 3a shows the discrimination score S as a function of the parameter α representing the basal reproduction activity. As shown in the figure, in the case without Treg cells, the discrimination score S has a peak around α ∼ 0.2. However, the maximum value of S is significantly smaller than in the case with Treg cells, indicating lower discrimination accuracy in the case without Treg cells. Fig 3b shows the number of Tconv cells in the case without Treg as a function of rt, where the parameter α is set to 0.1 which is close to that which results in the maximum value of S. As shown, the increase in Tconv cell number occurs in both cases of self and non-self antigen presentations, and thus the clear self/non-self discrimination as in Fig 2a is difficult. We have performed numerical experiments using various different parameter sets and confirmed that as long as the affinity distributions of TCRs to self and non-self antigens have a significant overlap as in Fig 1b, the maximum discrimination score is generally smaller in the case without Treg cells than in that with Treg cells, as shown in S1 Fig. The results suggested that when the affinity bias is small, clear self/non-self discrimination as in Fig 2 is possible only with the aid of Treg regulation.


Robust and Accurate Discrimination of Self/Non-Self Antigen Presentations by Regulatory T Cell Suppression
Self/non-self discrimination accuracy.(a) The discrimination score S as a function of basal reproduction activity α. (b) The average number of Tconv cells in the case without Treg regulation. The reproduction activity α is set to 0.1 at which the discrimination score becomes maximum. The parameters are set to those used in Fig 2, except for α.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036821&req=5

pone.0163134.g003: Self/non-self discrimination accuracy.(a) The discrimination score S as a function of basal reproduction activity α. (b) The average number of Tconv cells in the case without Treg regulation. The reproduction activity α is set to 0.1 at which the discrimination score becomes maximum. The parameters are set to those used in Fig 2, except for α.
Mentions: It should be stressed that, without the regulation of cell proliferation by Treg cells, the clear self/non-self discrimination such as in Fig 2 is difficult when the negative selection is imperfect. To demonstrate this, we simulated the response to self or non-self antigen presentations when there are no Treg cells and where the affinity distribution of Tconv is identical to that in Fig 1b (ΔTconv = 0.75 and σ = 1). To evaluate the accuracy of self/non-self discrimination, we define the discrimination score as follows:S≡∫012{⟨Nns(rt)⟩-⟨Ns(rt)⟩}drt.(2)Here, 〈Ns(rt)〉 and 〈Nns(rt)〉 represent the average numbers of Tconv cells when a self or a non-self target antigen is presented in the ratio rt, respectively, where the average is taken over various target antigens. This discrimination score corresponds to the area between the curves of self and non-self antigen presentations in Fig 2a, which takes a larger value when the system can discriminate self and non-self antigens accurately. Fig 3a shows the discrimination score S as a function of the parameter α representing the basal reproduction activity. As shown in the figure, in the case without Treg cells, the discrimination score S has a peak around α ∼ 0.2. However, the maximum value of S is significantly smaller than in the case with Treg cells, indicating lower discrimination accuracy in the case without Treg cells. Fig 3b shows the number of Tconv cells in the case without Treg as a function of rt, where the parameter α is set to 0.1 which is close to that which results in the maximum value of S. As shown, the increase in Tconv cell number occurs in both cases of self and non-self antigen presentations, and thus the clear self/non-self discrimination as in Fig 2a is difficult. We have performed numerical experiments using various different parameter sets and confirmed that as long as the affinity distributions of TCRs to self and non-self antigens have a significant overlap as in Fig 1b, the maximum discrimination score is generally smaller in the case without Treg cells than in that with Treg cells, as shown in S1 Fig. The results suggested that when the affinity bias is small, clear self/non-self discrimination as in Fig 2 is possible only with the aid of Treg regulation.

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.