IL-2 silencing enables Tfh cell expansion during vaccination but is redundant for antibody production

Abstract

Vaccines stimulate protective humoral immunity by coordinating lymphocyte activity in the germinal center (GC) response. However, the degree of protection varies across the population, with older individuals often showing lower titer antibody responses to vaccines. Previous work has correlated increased exposure to Th1 cytokines, like IL-2, with poor antibody responses in aging. Whether this is a causal relationship is unknown. Here we used Il2^cre/+; Rosa26^{stop-flox-Il2/+} mice, which cannot shut down IL-2 production once initiated, to test the hypothesis that sustained IL-2 exposure affects the GC response and antibody production post vaccination. Prolonged IL-2 production impeded T follicular helper (Tfh) cell differentiation, with reduced numbers of GC Tfh, pre-Tfh and T follicular regulatory cells consistently observed in the draining lymph node of Il2^cre/+; Rosa26^{stop-flox-Il2/+} mice at day 10 post immunization, relative to control mice. Numbers of Tfh cells remained suppressed at day 21 post immunization and corresponded with reduced GC B cell formation, including NP-specific IgG1⁺ class-switched GC B cells. As a core output of the GC response, B220^-IRF4⁺CD138⁺ antibody-secreting cells (ASCs) were significantly reduced in the bone marrow of Il2^cre/+; Rosa26^{stop-flox-Il2/+} mice, 10 days post NP-KLH immunization compared to control mice. However, by day 21, antigen-specific humoral immunity was restored, with similar levels of B220^-IRF4⁺CD138⁺ and NP-specific ASCs in both experimental and control groups. In summary, while sustained IL-2 production delayed Tfh differentiation and early GC formation, it did not affect overall antibody titers after vaccination.

Keywords: Germinal center; IL‐2; T‐follicular helper; vaccination.