# Altered Cytokine‐Induced STAT3 and STAT5 Activation of Peripheral T Follicular Helper Cells Contributes to Vaccine‐Non‐Responsiveness in Aging and HIV

## TL;DR

This study shows that changes in immune cell signaling in older adults and people with HIV reduce vaccine effectiveness by altering T cell responses.

## Contribution

The study identifies altered IL-2-induced STAT5 and IL-21-induced STAT3 signaling in pTfh cells as a mechanism for vaccine non-responsiveness in aging and HIV.

## Key findings

- Older individuals and those with HIV show increased IL-2-induced STAT5 activity in pTfh cells.
- IL-2-induced STAT5 in pTfh cells correlates inversely with vaccine antibody titers.
- Altered STAT signaling in pTfh cells may hinder Tfh differentiation and vaccine responses.

## Abstract

Previous studies from our lab identified functional defects in antigen‐specific peripheral T follicular helper cells (pTfh), characterized by low IL‐21 and high IL‐2 production, contributing to non‐responsiveness to the influenza vaccine in both aging and HIV. This study investigated how IL‐21‐induced STAT3 and IL‐2‐induced STAT5 activation in pTfh cells affects vaccine responses in aging people with HIV (PWH) and those without HIV (PWoH). Ninety participants, including young (Y, ≤ 40 years) and old (O, ≥ 65 years) PWoH (YPWoH, n = 23; OPWoH, n = 25) and virally suppressed PWH (YPWH, n = 19; OPWH, n = 23), received the seasonal quadrivalent influenza vaccine. Samples were collected at pre‐vaccination (day 0) and at days 14 and 28 post‐vaccination. Participants were classified as vaccine responders (VR) or non‐responders (VNR) based on serum antibody titers against vaccine antigens using the hemagglutination inhibition assay. Phosphoflow cytometry was performed on pre‐vaccination PBMCs stimulated with IL‐21 or IL‐2, and high‐dimensional analysis was performed using OMIQ software. Peripheral Tfh cells of young individuals showed greater IL‐21‐induced STAT3, reduced IL‐2‐induced STAT5 activity, and a reduced frequency of IL‐2R+ pTfh cells compared to older individuals. IL‐21‐induced STAT3 in naïve CD4+ T cells in young participants correlated with the frequency of pTfh cells. Among VNR, IL‐2‐induced STAT5 in pTfh cells inversely correlated with day 28 vaccine titers. Our findings emphasize the essential role of IL‐21 and IL‐2‐induced STAT signaling in orchestrating the immune response to vaccination. As individuals age, IL‐2‐induced STAT5 signaling in pTfh increases, potentially hindering Tfh cell differentiation and function, which may result in weaker vaccine responses.

Chronic immune activation and inflammation associated with aging and HIV skew Tfh signaling toward enhanced IL‐2–STAT5 activation, reinforcing IL‐2R expression through a positive feedback loop and suppressing Tfh helper differentiation programs, thereby contributing to impaired vaccine responsiveness.