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

Young individuals showed greater IL-21-induced STAT3 activity and reduced IL-2-induced STAT5 activity in peripheral T follicular helper cells compared to older individuals.

• Ninety participants were studied: YPWoH (n=23), OPWoH (n=25), YPWH (n=19), and OPWH (n=23)
• Young participants were defined as ≤40 years and old participants as ≥65 years
• Phosphoflow cytometry was performed on pre-vaccination PBMCs stimulated with IL-21 or IL-2
• High-dimensional analysis was performed using OMIQ software

Young individuals had a reduced frequency of IL-2 receptor positive (IL-2R+) pTfh cells compared to older individuals.

• This finding was observed across both PWoH and PWH groups
• The reduction in IL-2R+ pTfh frequency in young individuals was associated with lower IL-2-induced STAT5 signaling
• This pattern was identified using pre-vaccination PBMC samples collected at day 0

IL-21-induced STAT3 activation in naïve CD4+ T cells in young participants correlated with the frequency of pTfh cells.

• This correlation was identified in pre-vaccination samples
• The finding suggests that IL-21/STAT3 signaling in naïve CD4+ T cells may support pTfh cell differentiation or maintenance
• Analysis was performed using phosphoflow cytometry on pre-vaccination PBMCs

Among vaccine non-responders (VNR), IL-2-induced STAT5 activity in pTfh cells inversely correlated with day 28 vaccine antibody titers.

• Vaccine responders and non-responders were classified based on serum antibody titers using the hemagglutination inhibition (HAI) assay
• Samples were collected at pre-vaccination (day 0) and at days 14 and 28 post-vaccination
• The inverse correlation between STAT5 activation and vaccine titers was specific to the VNR group
• The vaccine used was the seasonal quadrivalent influenza vaccine

Previous work from the same laboratory identified functional defects in antigen-specific pTfh cells characterized by low IL-21 and high IL-2 production contributing to influenza vaccine non-responsiveness in both aging and HIV.

• These defects were observed in both aging people without HIV (PWoH) and virally suppressed people with HIV (PWH)
• The current study builds on these prior findings by examining downstream STAT signaling pathways
• All PWH participants in the current study were virally suppressed

Increased IL-2-induced STAT5 signaling in pTfh cells with aging potentially hinders Tfh cell differentiation and function, contributing to weaker vaccine responses.

• This mechanism was proposed to explain vaccine non-responsiveness observed in both aging and HIV contexts
• The study emphasizes the essential role of IL-21 and IL-2-induced STAT signaling in orchestrating the immune response to vaccination
• Both aging (OPWoH) and aging people with HIV (OPWH) were examined, representing a combined aging and HIV model of immune dysfunction