Hypoxia activates the HIF complex (HIF-1α, HIF-1β, HIF-2α) to induce AID expression in B cells independently of cytokine signaling. However, hypoxia alone is insufficient to trigger class switch recombination (CSR), which additionally requires cytokine-driven chromatin accessibility, highlighting a mechanistic uncoupling between AID induction and functional antibody diversification.
ABSTRACT
Hypoxia has been shown to shape the humoral immune response within germinal centers, where B cells diversify their receptors through somatic hypermutation (SHM) and class switch recombination (CSR). Both processes are initiated by activation-induced cytidine deaminase (AID), which deaminates cytosines into uracils in immunoglobulin genes, leading to point mutations during SHM or to double-stranded DNA breaks during CSR. Although AID’s function is well characterized, the mechanisms governing its expression remain ill-defined. We previously identified the hypoxia-inducible transcription factor (HIF) transcription complex (comprised of HIF-1α, HIF-1β, and the auxiliary subunits HIF-2α and HIF-3α) as a regulator of optimal AID expression during CSR. Indeed, loss of HIF-1α or HIF-1β delays AID expression and impairs CSR. Here, we examine the contribution of HIF-2α and HIF-3α. We show that deficiency in HIF-2α, but not HIF-3α, impairs CSR, whereas combined loss of HIF-1α and HIF-2α does not exacerbate the defect, indicating that HIF-1α is the dominant subunit driving this process. Importantly, we demonstrate that hypoxia can induce AID expression, independently of additional stimuli. Collectively, these findings reveal that hypoxia regulates AID expression in a context- and time-dependent manner through HIF activation. This underscores the central role of hypoxic signaling in antibody diversification and suggests broader implications for immune regulation and the onset of B-cell malignancies.