MacLean, A. J. | Search bioRxiv

bioRxiv2024

Affinity maturation of antibody responses is mediated by differential plasma cell proliferation

Increased antibody affinity over time after vaccination, known as affinity maturation, is a prototypical feature of immune responses. Recent studies have shown that a diverse collection of B cells, producing antibodies with a wide spectrum of different affinities, are selected into the plasma cell (PC) pathway. How affinity-permissive selection enables PC affinity maturation remains unknown. Here we report that PC precursors (prePC) expressing high affinity antibodies receive higher levels of T follicular helper (Tfh)-derived help and divide at higher rates than their lower affinity counterparts once they leave the GC. Thus, differential cell division by selected prePCs accounts for how diverse precursors develop into a PC compartment that mediates serological affinity maturation.

immunology↗

bioRxiv2023

Integration of Avidity and Differentiation is enabled by CD8+ T-cell sensing of IFN-γ

The most effective responses to intracellular pathogens have a breadth of T-cell clones with different affinities for their cognate peptide, and a diversity of functional phenotypes, from effector to long-lived memory cells. While high- and low-affinity T-cells are inherently skewed towards becoming effector and memory, respectively, overall, both functional subsets exploit a wide range of affinities. How the breadth of affinities and functionalities are coordinated is therefore unclear. In this study, we provide evidence that direct sensing of the cytokine IFN-{gamma} by CD8+ T-cells is a factor controlling the integration of T-cell affinity and differentiation during infection. IFN-{gamma} increases the expansion of low-affinity T-cells, allowing them to overcome the selective advantage of high-affinity T-cells. Concomitantly, IFN-{gamma} reinforces high-affinity T-cell entry into the memory pool. As a result, direct IFN-{gamma} sensing by CD8+ T-cells increases the avidity of the memory response. This comes at the expense of the primary T-cell response, for which IFN-{gamma} decreases the avidity, leading to sub-optimum immunity to infection. IFN-{gamma} sensing by CD8+ T-cells is paracrine, provided by a distinct subset of CD8+ T-cells called Virtual Memory T-cells, an antigen inexperienced subset that harbors memory features. Overall, we propose that IFN-{gamma} and Virtual Memory T-cells fulfil a critical immunoregulatory role by enabling the coordination of T-cell avidity and fate.

immunology↗