How persistent infection overcomes peripheral tolerance mechanisms to cause T cell-mediated autoimmune disease

Abstract

T cells help orchestrate immune responses to pathogens, and their aberrant regulation can trigger autoimmunity. Recent studies highlight that a threshold number of T cells (a quorum) must be activated in a tissue to mount a functional immune response. These collective effects allow the T cell repertoire to respond to pathogens while suppressing autoimmunity due to circulating autoreactive T cells. Our computational studies show that increasing numbers of pathogenic peptides targeted by T cells during persistent or severe viral infections increase the probability of activating T cells that are weakly reactive to self-antigens (molecular mimicry). These T cells are easily re-activated by the self-antigens and contribute to exceeding the quorum threshold required to mount autoimmune responses. Rare peptides that activate many T cells are sampled more readily during severe/persistent infections than in acute infections, which amplifies these effects. Experiments in mice to test predictions from these mechanistic insights are suggested.

Keywords: T cells; autoimmunity; immunology.

Fig. 1.

Schematic depiction of how quorum sensing by T cells can result in functional immune responses to pathogen-derived pMHC molecules and not host-derived ones in spite of the existence of autoreactive T cells in the mature repertoire. For the case depicted, the quorum number is taken to be four.

Fig. 2.

Model for TCR–pMHC binding free energy. The variable residues of the TCR that interact with the peptide in the pMHC complex are represented by strings of amino acids. Dot product of pairwise interactions for the two strings provides the total binding free energy.

Fig. 3.

Steps in modeling infection: we follow the steps shown and described in the text for increasing numbers of pathogen-derived peptides (or epitopes), ${\text{N}}_{\text{f}}$, and the same number, ${\text{N}}_{\text{T}}$, of self-peptides to calculate the probability of a functional autoimmune response.

Fig. 4.

Antigen concentration versus % of B3K508 TCR Tg T cells population that are TNF$\alpha$ producers when exposed to 3K. The blue and orange curves are the responses of naive and activated cells, respectively.

Fig. 5.

(A) Probability of triggering autoimmunity, P(auto$\mid {\text{N}}_{\text{f}}$), as a function of the number of pathogen-derived peptides targeted for two different values of Q, $\text{Q}=1$ (no collective effects) and $\text{Q}=10$ (collective effects as per quorum model). (B) Probability of triggering autoimmunity, P(auto$\mid {\text{N}}_{\text{f}}$), normalized by the probability of triggering autoimmunity in the case of no infection, P(auto$\mid {\text{N}}_{\text{f}}$=0). Parameters used are as shown in SI Appendix, Table S2.

Fig. 6.

Collective effects in the quorum model confer robustness against autoimmunity. All simulations unless otherwise denoted were performed with the same parameters as in SI Appendix, Table S2. (A) Simulations were performed with $\text{M}=$8,000 and $\text{M}=$6,500 at increasing values of $\text{Q}$ at ${\text{N}}_{\text{f}}=10$. The calculated change in the probability of triggering autoimmunity, P(auto), is graphed as a function of Q. (B) Simulations were performed with ${\text{N}}_{\text{T}}=10$ and ${\text{N}}_{\text{T}}=20$ for increasing values of $\text{Q}$ at ${\text{N}}_{\text{f}}=10$. The calculated change in P(auto) is graphed as a function of Q.

Fig. 7.

Distribution of the number of T cells activated by pathogen-derived and self-peptides as obtained from the simpler coarse-grained model described in the text. A total of 9,995 self-peptides activated 0 T cells, 1 self-peptide activated between 1 and 10, and 4 self-peptides activated 10 or more. A total of 39,983 pathogen-derived peptides activated 0 T cells, 4 activated between 1 and 10, and 13 activated 10 or more.