Memory CD4⁺ T cells enhance B‐cell responses to drifting influenza immunization

Abstract

Influenza A annually infects 5-10% of the world's human population resulting in one million deaths. Influenza causes annual epidemics and reinfects previously exposed individuals because of antigenic drift in the glycoprotein hemagglutinin. Due to antigenic drift, the immune system is simultaneously exposed to novel and conserved parts of the influenza virus via vaccination and/or infection throughout life. Preexisting immunity has long been known to augment subsequent hemagglutination inhibitory antibody (hAb) responses. However, the preexisting immunological contributors that influence hAb responses are not understood. Therefore, we adapted and developed sequential infection and immunization mouse models using drifted influenza strains to show that MHC Class II haplotype and T-cell reactivity influences subsequent hAb responses. We found that CB6F1 mice infected with A/CA followed by immunization with A/PR8 have increased hAb responses to A/PR8 compared to C57BL/6 mice. Increased hAb responses in CB6F1 mice were CD4 + T-cell and B-cell dependent and corresponded to increased germinal center A/PR8-specific B and T-follicular helper cells. These results suggest conserved MHC Class II restricted epitopes within HA are essential for B cells to respond to drifting influenza and could be leveraged to boost hAb responses.Keywords: infectious diseases r influenza r preexisting immunity r vaccinology Additional supporting information may be found online in the Supporting Information section at the end of the article.

Chronic Viral Infection Promotes Efficient Germinal Center B Cell Responses

“…1We propose that the continuously high ASC output even at late time points after the onset of chronic infection warrants a better representation of the hypermutated GC B cell repertoire in the circulating serum antibody pool. Conversely, the hypermutated B cell pool emerging from acute infection would merely be available for accelerated nAb formation upon re-infection (Gage et al, 2019;Schweier et al, 2019). The observation that not only rCl13-infected, but also a few rARM-infected, mice mounted nAb responses ( Figure 1C, right panel), supports this concept.…”

Remote immune processes revealed by immune-derived circulating cell-free DNA

“…To test this hypothesis, we examined longitudinal blood samples from healthy individuals who received an annual quadrivalent influenza vaccination (Nakaya et al, 2011;Voigt et al, 2018). The influenza vaccine response is mediated mostly by the humoral immune system (B cells) aided by CD4 T-cells (Gage et al, 2018). Changes in circulating cell counts occur a week after vaccination, reflecting processes such as plasma cell formation (Victora and Wilson, 2015).…”

Chronic viral infection promotes efficient germinal center B cell responses

“…(1) We propose that the continuously high ASC output even at late time points after the onset of chronic infection warrants a better representation of the hypermutated GC B cell repertoire in the circulating serum antibody pool. Conversely, the hypermutated B cell pool emerging from acute infection would merely be available for accelerated nAb formation upon re-infection (Gage et al, 2019;Schweier et al, 2019). The observation that not only rCl13-infected, but also a few rARM-infected, mice mounted nAb responses (Figure 1C, right panel), supports this concept.…”