Transient immune landscape remodelling shapes CD8 T-cell priming during infection

Abstract

Immune responses to intracellular pathogens require the generation of a CD8 T-cell response comprised of clones with a broad range of T Cell Receptor (TCR) affinities for their cognate peptide. While high-affinity clones clear pathogens during initial infection, low-affinity T-cells are critical to protect against subsequent encounters with mutated pathogens. Low-affinity T-cells are recruited to an immune response despite known mechanisms that limit their expansion and priming. As such, the mechanism safeguarding the recruitment of low-affinity T-cell clones during infection remains unclear. Here, we show that at the start of an infection, the spatial immune architecture is transiently reorganised to initiate broad T-cell priming. In particular, Tregs become segregated from the initial priming site, resulting in a spatio-temporal window during which pathogen-specific T-cell priming is protected from Treg inhibition. Priming induces the expression of CXCR3 in a TCR affinity-dependent manner, which conditions the retention of activated T-cells in the priming region. Inability to express CXCR3 leads to T-cell relocation towards Treg-rich areas, where their expansion is limited by the lack of the costimulatory molecule CD70. Our study redefines the role of Treg during infection and provides a mechanism to explain how the priming and breadth of the CD8 T-cell response is protected during infection.