LAUSR

Analysis of influenza-specific B cells during antigen exposure and tissue compartmentalization provides insights into human B cell memory. Investigating influenza immunity Seasonal influenza vaccines have been recommended for decades, but studies focused on antigen-specific lymphocytes in humans are sparse. Koutsakos et al. examined longitudinal samples of influenza-vaccinated individuals to determine what responses generate protective immunity. Vaccination could induce circulating T follicular helper memory cells, antibody-secreting cells, and memory B cells, but did not seem to affect other types of lymphocytes. Existing anti-influenza antibodies at the time of vaccination dampened these responses. They probed different types of human tissues to hunt for influenza memory B cells, thereby showing that the memory response exists outside the circulation. Better targeting these cells could improve influenza vaccine efficacy. Immunization with the inactivated influenza vaccine (IIV) remains the most effective strategy to combat seasonal influenza infections. IIV activates B cells and T follicular helper (TFH) cells and thus engenders antibody-secreting cells and serum antibody titers. However, the cellular events preceding generation of protective immunity in humans are inadequately understood. We undertook an in-depth analysis of B cell and T cell immune responses to IIV in 35 healthy adults. Using recombinant hemagglutinin (rHA) probes to dissect the quantity, phenotype, and isotype of influenza-specific B cells against A/California09-H1N1, A/Switzerland-H3N2, and B/Phuket, we showed that vaccination induced a three-pronged B cell response comprising a transient CXCR5−CXCR3+ antibody-secreting B cell population, CD21hiCD27+ memory B cells, and CD21loCD27+ B cells. Activation of circulating TFH cells correlated with the development of both CD21lo and CD21hi memory B cells. However, preexisting antibodies could limit increases in serum antibody titers. IIV had no marked effect on CD8+, mucosal-associated invariant T, γδ T, and natural killer cell activation. In addition, vaccine-induced B cells were not maintained in peripheral blood at 1 year after vaccination. We provide a dissection of rHA-specific B cells across seven human tissue compartments, showing that influenza-specific memory (CD21hiCD27+) B cells primarily reside within secondary lymphoid tissues and the lungs. Our study suggests that a rational design of universal vaccines needs to consider circulating TFH cells, preexisting serological memory, and tissue compartmentalization for effective B cell immunity, as well as to improve targeting cellular T cell immunity.