Journal Article

Dysfunctional peripheral T follicular helper cells dominate in people with impaired influenza vaccine responses: Results from the FLORAH study

Pahwa, Savita, Pan, Li, Pallikkuth, Suresh, de Armas, Lesley R., Arheart, Kristopher L., Rinaldi, Stefano, Pahwa, Rajendra, George, Varghese K.

2019

Overview

Antigen-primed cluster of differentiation (CD) 4+ T follicular helper (Tfh) cells interact with B cells in the germinal centers (GCs) of lymph nodes to generate vaccine-induced antibody (Ab) responses. In the circulation, peripheral Tfh (pTfh) cells, a subset of memory CD4 T cells, serve as surrogates for GC Tfh because of several functional and phenotypic similarities between them. We investigated features of H1N1 influenza antigen-specific pTfh (Ag.pTfh) in virologically controlled HIV+ volunteers on antiretroviral therapy (ART) and healthy control (HC) participants selected from a seasonal influenza vaccine responsiveness study. Selection of the participants was made based on age, defined as young (18-40 y) and old (>60 y) and on their classification as a vaccine responder (VR) or vaccine nonresponder (VNR). VRs demonstrated expansion of CD40L+ and CD69+ Ag.pTfh, with induction of intracellular interleukin 21 (IL-21) and inducible costimulator (ICOS) post vaccination; these responses were strongest in young HC VRs and were less prominent in HIV+ individuals of all ages. Ag.pTfh in VNRs exhibited dramatically different characteristics from VRs, displaying an altered phenotype and a cytokine profile dominated by cytokines IL-2, tumor necrosis factor alpha (TNF-α), or IL-17 but lacking in IL-21. In coculture experiments, sorted pTfh did not support the B cell IgG production in VNRs and were predominantly an inflammatory T helper 1 (Th1)/T helper 17 (Th17) phenotype with lower ICOS and higher programmed cell death protein 1 (PD1) expression. Induction of IL-21 and ICOS on Ag.pTfh cells are negatively affected by both aging and HIV infection. Our findings demonstrate that dysfunctional Ag.pTfh cells with an altered IL-21/IL-2 axis contribute to inadequate vaccine responses. Approaches for targeting inflammation or expanding functional Tfh may improve vaccine responses in healthy aging and those aging with HIV infection.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acquired immune deficiency syndrome / Adult / Age / Aging / AIDS / Analysis / Antibodies / Antibodies, Viral - immunology / Antigens / Antigens, Viral - immunology / Antiretroviral agents / Antiretroviral therapy / Apoptosis / B-Lymphocytes - immunology / Biology and Life Sciences / CD4 antigen / CD4 lymphocytes / CD40L protein / CD69 antigen / Cell death / Cell Proliferation / Chemokines / Complications and side effects / Cytokines / Cytokines - metabolism / Cytomegalovirus / Discriminant analysis / Female / Generalized linear models / Germinal centers / Globular clusters / Health care / Helper cells / HIV / HIV Infections - immunology / Human immunodeficiency virus / Humans / Immunoglobulin G / Immunological memory / Immunology / Inducible T-Cell Co-Stimulator Protein - metabolism / Infections / Inflammation / Inflammation Mediators - metabolism / Influenza / Influenza A Virus, H1N1 Subtype / Influenza vaccines / Influenza Vaccines - immunology / Influenza, Human - immunology / Interleukin / Interleukin 17 / Interleukin 2 / Interleukin 21 / Interleukin-2 - metabolism / Interleukins - metabolism / Lymph nodes / Lymphocyte Activation - immunology / Lymphocyte Count / Lymphocytes / Lymphocytes B / Lymphocytes T / Male / Medical research / Medicine / Medicine and Health Sciences / Medicine, Experimental / Memory cells / Neutralization Tests / PD-1 protein / Phenotype / Phenotypes / Public health / Studies / T-Lymphocytes, Helper-Inducer - immunology / Tumor Necrosis Factor-alpha - metabolism / Tumor necrosis factor-α / Vaccination / Vaccines / Young Adult