Affinity gaps among B cells in germinal centers drive the selection of MPER precursors.
Rashmi RayTorben SchiffnerXuesong WangYu YanKimmo RantalainenChang-Chun David LeeShivang ParikhRaphael A ReyesGordon A DaleYing-Cing LinSimone PecettaSophie GiguèreOlivia SwansonSven KratochvilEleonora MelziIvy PhungLisa MadungweOleksandr KalyuzhniyJohn WarnerStephanie R WeldonRyan TingleEdward LampertiKathrin H KirschNicole PhelpsErik GeorgesonYumiko AdachiMichael KubitzUsha NairShane CrottyIan A WilsonWilliam R SchiefFacundo D BatistaPublished in: Nature immunology (2024)
Current prophylactic human immunodeficiency virus 1 (HIV-1) vaccine research aims to elicit broadly neutralizing antibodies (bnAbs). Membrane-proximal external region (MPER)-targeting bnAbs, such as 10E8, provide exceptionally broad neutralization, but some are autoreactive. Here, we generated humanized B cell antigen receptor knock-in mouse models to test whether a series of germline-targeting immunogens could drive MPER-specific precursors toward bnAbs. We found that recruitment of 10E8 precursors to germinal centers (GCs) required a minimum affinity for germline-targeting immunogens, but the GC residency of MPER precursors was brief due to displacement by higher-affinity endogenous B cell competitors. Higher-affinity germline-targeting immunogens extended the GC residency of MPER precursors, but robust long-term GC residency and maturation were only observed for MPER-HuGL18, an MPER precursor clonotype able to close the affinity gap with endogenous B cell competitors in the GC. Thus, germline-targeting immunogens could induce MPER-targeting antibodies, and B cell residency in the GC may be regulated by a precursor-competitor affinity gap.
Keyphrases
- human immunodeficiency virus
- cancer therapy
- hepatitis c virus
- antiretroviral therapy
- dna repair
- capillary electrophoresis
- gas chromatography
- mouse model
- hiv aids
- mass spectrometry
- drug delivery
- dna damage
- oxidative stress
- medical students
- zika virus
- hiv testing
- men who have sex with men
- high resolution
- emergency medicine