Nicole M. Arroyo-Diaz, PhD Student

Lung-resident memory B cells (lung-BRMs) differentiate into plasma cells after reinfection, providing enhanced pulmonary protection.

A research team led by PhD student Nicole M. Arroyo-Díaz and directed by Andre Ballesteros-Tato, PhD  investigated the determinants of lung-BRM differentiation upon influenza infection. Kinetic analyses revealed that influenza nucleoprotein (NP)-specific BRMs differentiated early after infection and required T follicular helper (Tfh) cell help. BRM differentiation coincided with transient interferon (IFN)-γ production by Tfh cells.

Depletion of IFN-γ in Tfh cells prevented lung-BRM differentiation and impaired protection against heterosubtypic infection. IFN-γ was required for expression of the transcription factor T-bet by germinal center (GC) B cells, which promoted differentiation of a CXCR3+ GC B cell subset. The absence of IFN-γ signaling or T-bet in GC B cells prevented CXCR3+ pre-memory precursor development and hampered CXCR3+ memory B cell differentiation and subsequent lung-BRM responses.

The team’s work revealed that intrinsic IFN-γ signaling in GC B cells was required for the development of lung-BRMs after influenza virus infection. Correspondently, in the absence of IFN-γ-producing Tfh cells, lung-BRMs were not generated, and lung-BRM-mediated protection after heterologous rechallenge was compromised. Their results identify IFN-γ as a critical regulator of lung-BRM differentiation and demonstrate that IFN-γ-producing Tfh cells are essential for generating protective lung-BRM responses after influenza virus infection.

The research team’s data provide evidence of a critical role for IFN-γ-producing Tfh cells, as well as new insights into the mechanisms that fine-tune GC B cell fate decisions after influenza virus infection. These discoveries will be essential for designing new vaccine strategies tailored to elicit potent lung-BRM responses.

Read the full text as published in the journal Immunity.