Human circulating influenza-CD4 ⁺ ICOS1 ⁺ IL-21 ⁺ T cells expand after vaccination, exert helper function, and predict antibody responses

Abstract

Protection against influenza is mediated by neutralizing antibodies, and their induction at high and sustained titers is key for successful vaccination. Optimal B cells activation requires delivery of help from CD4 + T lymphocytes. In lymph nodes and tonsils, T-follicular helper cells have been identified as the T cells subset specialized in helping B lymphocytes, with interleukin-21 (IL-21) and inducible costimulatory molecule (ICOS1) playing a central role for this function. We followed the expansion of antigen-specific IL-21 + CD4 + T cells upon influenza vaccination in adults. We show that, after an overnight in vitro stimulation, influenza-specific IL-21 + CD4 + T cells can be measured in human blood, accumulate in the CXCR5 − ICOS1 + population, and increase in frequency after vaccination. The expansion of influenza-specific ICOS1 + IL-21 + CD4 + T cells associates with and predicts the rise of functionally active antibodies to avian H5N1. We also show that blood-derived CXCR5 − ICOS1 + CD4 + T cells exert helper function in vitro and support the differentiation of influenza specific B cells in an ICOS1-and IL-21-dependent manner. We propose that the expansion of antigen-specific ICOS1 + IL-21 + CD4 + T cells in blood is an early marker of vaccine immunogenicity and an important immune parameter for the evaluation of novel vaccination strategies.CD4 help | predictivity | humoral response T o confer protection, human vaccines rely on the induction of neutralizing antibodies and on the generation of a pool of memory lymphocytes able to mount an accelerated response upon encounter with the target pathogen. In recent years, novel vaccines, adjuvants, and delivery systems that are able to improve vaccine immunogenicity while reducing their reactogenicity have been developed. As vaccines are given to healthy subjects, their development is a challenging endeavor that requires extensive studies to assess safety, immunogenicity, and clinical efficacy. To accelerate the screening of novel candidates, research has focused on the identification of early biomarkers, molecular and transcriptional signatures predicting vaccine efficacy (1). Predictors should be easy to test in large clinical trials and have a clear mechanistic relationship with the correlates or surrogates of protection taken as the study endpoint. We have previously shown that an early postvaccination increase in the number of vaccine-specific CD4 + T cells is correlated in a predictive manner with the rise and long-term maintenance of protective antibody titers to avian influenza (2). The aim of the present study was to characterize the CD4 + T cells subset responsible for this function.T follicular helper (Tfh) cells have been identified in lymph nodes and tonsils as the CD4 + T cells subpopulation specialized in providing help to B cells (3-11). The recent identification of a circulating counterpart of this T cells subset in blood led us to investigate whether vaccine-specific IL-21 + CD4 + T cells are detectable in human blood, if their frequency is...

Circulating Follicular Regulatory T Cells Are Defective in Multiple Sclerosis

“…3B), whereas the percentage of naive T FR (CD45RO 2 CD45RA + ) decreased significantly after 1 and 7 d (p = 0.01, data not shown). In line with other groups (21,22), we confirmed a significant increase in circulating T FH after vaccination (all time points, p , 0.001; Fig. 3C).…”

Longevity and Determinants of Protective Humoral Immunity after Pandemic Influenza Infection

“…1 T follicular helper cells are specialized for providing cognate B cell help and after influenza vaccination, it is the induction of these cells, rather than preexisting frequencies, that is associated with antibody induction (28,29). Interestingly, work in animal models revealed that IL-2 suppresses the differentiation of T follicular helper cells and negatively impacts influenza-specific long-lived antibody responses, a finding consistent with our observation (30,31).…”

Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans

“…For example, blocking IL-21, ICOS, or CD40L with mAbs might increase either T-cell responsive infections or the rate of leukemia relapse as a result of dampening of peripheral immune surveillance mechanisms. Finally, our discovery that Tfh cells are upregulated in murine cGVHD warrants investigation of this cell population in the peripheral blood 35 of cGVHD patients. If correlations are noted with cGVHD onset or severity, Tfh cells could be targeted, as we have done in this study, which may prove useful for treating or perhaps preventing cGVHD in the clinic.…”