Class switch recombination articles from across Nature Portfolio

Immunoglobulins sample vast swathes of primary sequence and conformational space to generate and select B cell clones with exquisite selectivity and affinity for specific antigens. This Perspective article examines the interplay between antibody diversification mechanisms and highlights the importance of constant regions in influencing the specificity and functionality of individual antibodies.

Here the authors reveal that in addition to promoting class switch recombination via inhibition of DNA end processing, RIF1 fine-tunes the kinetics of plasma cell differentiation, thus providing an additional layer of control in the establishment of humoral immunity.

Identification of specificity from antibody sequence is challenging especially when different clonotype lineages recognise antigens similarly in a process of convergence. Here using TREM2 reactive antibodies in rats as an example the authors characterise convergent antibodies and identify similarities in recognition between different lineages.

Antibody diversification relies on the intentional mutagenesis of immunoglobulin genes for adaptive immune responses. Here, the authors identified a CTLH E3 ubiquitin ligase complex that co-opts FAM72A to recruit and degrade the UNG2 base excision repair factor to permit mutagenesis.

Humanized mice have been a valuable tool for modeling human immunology but are limited in their ability to model human antibody responses. Here the authors present their THX humanized mouse that does model human antibody responses and test its suitability for vaccination and autoimmunity studies.

B cell activation and differentiation entails metabolic remodelling, involving differential utilisation of monocarboxylates such as L-lactate and pyruvate. Here authors show by B-cell-specific genomic deletion of monocarboxylate transporter 1 (MCT1) that the consequential scarcity of pyruvate results in decreased acetylation of Histone H3 at K27, leading to decreased AID transcription and deficient class switching to IgG.

Nelson et al. report that lung-resident IgG1⁺ memory B cells class-switch to IgE to mediate airway hypersensitivity in asthma.

A single-cell sequencing study shows that the human memory B cell repertoire is dominated by large IgM, IgG2 and IgA immunoglobulin families, whereas IgG1 families, including those specific for recall antigens, are of a small size. Multi-year analysis shows that memory B cell families are highly stable and that plasmablasts of T cell–independent and T cell–dependent isotypes are produced in a recurrent manner.

Class-switch recombination was thought to take place in B cells that enter germinal centres, but this study shows that it actually occurs earlier than previously thought.

Shieldin is a newly characterized protein complex that functions downstream of 53BP1 in promoting NHEJ