Huseby, E. | bioRxiv Science

bioRxiv2023

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

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.

immunology↗

bioRxiv2022

Peptide Avidity for TCR on CD4 Effectors Determines the Extent of Memory Generation

The impact of initial peptide antigen affinity for TCR in driving memory fate has been studied previously, however its contributions when effectors contract to memory is unclear. To become memory, effector CD4 T cells must recognize antigen at 5-8 days post-infection, at what we call the "effector checkpoint." We examined whether peptide affinity for the TCR of effectors impacts the extent of memory and degree of protection against rechallenge. We made an influenza A virus (IAV) nucleoprotein (NP)-specific TCR transgenic strain, FluNP, and generated NP-peptide variants that bind FluNP TCR with a broad range of avidity. To vary avidity in vivo, we primed naive donor FluNP in IAV-infected hosts, purified 6d FluNP effectors and co-transferred them with peptide-pulsed APC into uninfected second hosts. Higher affinity peptides yielded higher numbers of FluNP memory cells in the spleen and most dramatically in the lung and dLN, and drove better protection against lethal influenza infection. The major impact of avidity was on memory cell number, not cytokine production, and was already apparent within several days of transfer. We previously showed that autocrine IL-2 production during the effector checkpoint prevented default effector apoptosis and supported memory formation. Here, peptide avidity determined the level of IL-2 produced by effectors. IL-2R expression by APC drove more memory cell formation, suggesting that transpresentation of IL-2 by APC at this checkpoint enhanced CD4 memory generation. Secondary memory generation was also avidity-dependent. We propose this pathway selects CD4 effectors of highest affinity to progress to memory.

immunology↗