Circulating T _FH cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity

Abstract

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 (T) 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 CXCR5CXCR3 antibody-secreting B cell population, CD21CD27 memory B cells, and CD21CD27 B cells. Activation of circulating T cells correlated with the development of both CD21 and CD21 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 (CD21CD27) 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 T cells, preexisting serological memory, and tissue compartmentalization for effective B cell immunity, as well as to improve targeting cellular T cell immunity.

Influenza-specific effector memory B cells predict long-lived antibody responses to vaccination in humans

“…Using fluorochrome labeled tetramer or monomer reagents, hemaggulutinin (HA)-specific Bmems have been identified within one month after IIV. 19–21 This antigen-specific Bmem compartment after IIV has been described as heterogeneous, comprising typical and atypical memory B cells. 19–21 We wanted to assess the phenotype and kinetics of the HA-specific Bmem compartment after IIV and the relationship of this compartment to the plasmablast and long-lived antibody (Ab) response.…”

T follicular helper cell heterogeneity: Time, space, and function

“…Since then, subsets of CD4 + T cells with "Tfhlike" characteristics, frequently referred to as circulating Tfh (cTfh) increase of a CXCR3+ population of cTfh cells that correlates with increase in high-avidity antibodies. 112,113 Induction of cTfh cells has also been observed in volunteers receiving in-trial HIV vaccines and a novel Escherichia coli vaccine. [114][115][116] Patients with autoimmunity such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome have increased frequency of cTfh cells with an "activated" phenotype which correlates with disease activity.…”

The IL‐12‐STAT4 axis in the pathogenesis of human systemic lupus erythematosus

“…Tfh1 cells are also present outside the GCs in human tonsils [52], and Tfh1 cells therefore might interact with naïve B cells outside GCs and promote their differentiation toward CD11c + DN B cells. Studies on influenza vaccines showed that an increase of activated Tfh1 cells in the blood correlated with the emergence of CD27 + CD38 + PBs in the blood [53] as well as a precursor of ASCs sharing properties with CD11c + DN B cells (though CD27 + ) [54,55], further supporting the potential role of Tfh1 cells in the generation of ASCs and CD11c + DN B cells [56]. Intriguingly, a recent study showed that exaggerated activity of Tfh2 cells co-expressing IL-21 and IL-4 is involved in SLE pathogenesis [57].…”