IL-21 enhances influenza vaccine responses in aged macaques with suppressed SIV infection.

Daniel Kvistad,Francois Villinger,Rajendra Pahwa,Suresh Pallikkuth,Savita Pahwa,Constantinos Petrovas,Alexander Kizhner,Tirupataiah Sirupangi

doi:10.1172/jci.insight.150888

Abstract

Natural aging and HIV infection are associated with chronic low-grade systemic inflammation, immune senescence, and impaired antibody responses to vaccines such as the influenza (flu) vaccine. We investigated the role of IL-21, a CD4+ T follicular helper cell (Tfh) regulator, on flu vaccine antibody response in nonhuman primates (NHPs) in the context of age and controlled SIV mac239 infection. Three doses of the flu vaccine with or without IL-21–IgFc were administered at 3-month intervals in aged SIV+ NHPs following virus suppression with antiretroviral therapy. IL-21–treated animals demonstrated higher day 14–postboost antibody responses, which associated with expanded CD4+ T central memory cells and peripheral Tfh–expressing (pTfh–expressing) T cell immunoreceptor with Ig and ITIM domains (TIGIT), expanded activated memory B cells, and contracted CD11b+ monocytes. Draining lymph node (LN) tissue from IL-21–treated animals revealed direct association between LN follicle Tfh density and frequency of circulating TIGIT+ pTfh cells. We conclude that IL-21 enhances flu vaccine–induced antibody responses in SIV+ aged rhesus macaques (RMs), acting as an adjuvant modulating LN germinal center activity. A strategy to supplement IL-21 in aging could be a valuable addition in the toolbox for improving vaccine responses in an aging HIV+ population.

Highlights

Impaired immunity in advancing age has been widely described [1,2,3,4,5,6] and is characterized by an increased susceptibility to infection and compromised efficacy of vaccination to generate antibody responses [7]
Given that CD4+ Tcm cells and peripheral Tfh (pTfh) provide critical help to B cells for differentiation and memory, we investigated if a relationship exists between activated memory (AM) B cells and the expanded frequencies and expression of TIGIT+CD4+ Tcm and TIGIT+ pTfh cells observed in IL-21–treated animals
These findings indicate that the relative degree of germinal center (GC) activity as a function of follicular T follicular helper cell (Tfh) density can be predicted by frequencies of TIGIT+CD4+ Tcm, TIGIT+ pTfh, and TIGIT+PD-1+ pTfh at the time of vaccination, and that IL-21 priming prior to vaccination induces expansion of said circulating CD4+ T cell subsets and subsequent increased follicular Tfh density

Summary

Introduction

Impaired immunity in advancing age has been widely described [1,2,3,4,5,6] and is characterized by an increased susceptibility to infection and compromised efficacy of vaccination to generate antibody responses [7]. The impact of persistent chronic inflammation in chronic ART–experienced virally suppressed HIV+ individuals was recently highlighted by our observation that higher prevaccination frequencies of CD11b-expressing inflammatory monocytes in HIV-infected individuals correlates with poor antibody response to seasonal influenza vaccination [18]. Strategies to improve vaccine-induced antibody responses and ameliorate chronic inflammation in aged HIV-infected persons must be explored

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