TY - JOUR
T1 - Circulating TFH cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity
AU - Koutsakos, Marios
AU - Wheatley, Adam K.
AU - Loh, Liyen
AU - Clemens, E. Bridie
AU - Sant, Sneha
AU - Nüssing, Simone
AU - Fox, Annette
AU - Chung, Amy W.
AU - Laurie, Karen L.
AU - Hurt, Aeron C.
AU - Rockman, Steve
AU - Lappas, Martha
AU - Loudovaris, Thomas
AU - Mannering, Stuart I.
AU - Westall, Glen P.
AU - Elliot, Michael
AU - Tangye, Stuart G.
AU - Wakim, Linda M.
AU - Kent, Stephen J.
AU - Nguyen, Thi H.O.
AU - Kedzierska, Katherine
N1 - Funding Information:
This work was supported by NHMRC program grants ID1071916 (K.K.) and ID1052979 (S.J.K.) and NHMRC project grants ID1129099 (A.K.W.) and ID1125164 (A.W.C.). M.K. and S.N. are supported by a Melbourne International Research Scholarship and Melbourne International Fee Remission Scholarship (MIFRS). E.B.C. is an NHMRC Peter Doherty Fellow. S.S. is supported by the Victoria-India Doctoral Scholarship and MIFRS. World Health Organization (WHO) Collaborating Centre for Reference Research on Influenza is supported by the Australian Government Department of Health. S.I.M. is supported by Juvenile Diabetes Research Foundation (JDRF) Career Development Award (5-CDA-2014-210-A-N) and NHMRC (ID1123586). M.L. is supported by a Career Development Fellowship from NHMRC (ID1047025). S.R. is an employee of Seqirus Ltd. S.G.T. is supported by NHMRC program and project grants. S.G.T., S.J.K., and K.K. are NHMRC Research Fellows.
Funding Information:
Human experimental work was conducted according to the Declaration of Helsinki Principles and to the Australian National Health and Medical Research Council (NHMRC) Code of Practice. Signed informed consent was obtained from all blood and tissue donors before the study. Tissues from deceased organ donors were obtained after written informed consent from the next of kin. The study was approved by the University of Melbourne Human Ethics Committee (ID 1443389.3 and 1443540), the Mercy Health Human Research Ethics Committee (ID R14/25), and the Australian Red Cross Blood Service (ARCBS) Ethics Committee (ID 2015#8).
Publisher Copyright:
Copyright © 2018 The Authors., some rights reserved.
PY - 2018/2/14
Y1 - 2018/2/14
N2 - Immunization with the inactivated influenza vaccine (IIV) remains the most effective strategy to combat seasonal influenza infections. IIV activates B cells and T follicular helper (TFH) cells and thus engenders antibody-secreting cells and serum antibody titers. However, the cellular events preceding generation of protective immunity in humans are inadequately understood. We undertook an in-depth analysis of B cell and T cell immune responses to IIV in 35 healthy adults. Using recombinant hemagglutinin (rHA) probes to dissect the quantity, phenotype, and isotype of influenza-specific B cells against A/California09-H1N1, A/Switzerland-H3N2, and B/Phuket, we showed that vaccination induced a three-pronged B cell response comprising a transient CXCR5-CXCR3+ antibody-secreting B cell population, CD21hiCD27+ memory B cells, and CD21loCD27+ B cells. Activation of circulating TFH cells correlated with the development of both CD21lo and CD21hi memory B cells. However, preexisting antibodies could limit increases in serum antibody titers. IIV had no marked effect on CD8+, mucosal-associated invariant T, gd T, and natural killer cell activation. In addition, vaccine-induced B cells were not maintained in peripheral blood at 1 year after vaccination. We provide a dissection of rHA-specific B cells across seven human tissue compartments, showing that influenza-specific memory (CD21hiCD27+) B cells primarily reside within secondary lymphoid tissues and the lungs. Our study suggests that a rational design of universal vaccines needs to consider circulating TFH cells, preexisting serological memory, and tissue compartmentalization for effective B cell immunity, as well as to improve targeting cellular T cell immunity.
AB - Immunization with the inactivated influenza vaccine (IIV) remains the most effective strategy to combat seasonal influenza infections. IIV activates B cells and T follicular helper (TFH) cells and thus engenders antibody-secreting cells and serum antibody titers. However, the cellular events preceding generation of protective immunity in humans are inadequately understood. We undertook an in-depth analysis of B cell and T cell immune responses to IIV in 35 healthy adults. Using recombinant hemagglutinin (rHA) probes to dissect the quantity, phenotype, and isotype of influenza-specific B cells against A/California09-H1N1, A/Switzerland-H3N2, and B/Phuket, we showed that vaccination induced a three-pronged B cell response comprising a transient CXCR5-CXCR3+ antibody-secreting B cell population, CD21hiCD27+ memory B cells, and CD21loCD27+ B cells. Activation of circulating TFH cells correlated with the development of both CD21lo and CD21hi memory B cells. However, preexisting antibodies could limit increases in serum antibody titers. IIV had no marked effect on CD8+, mucosal-associated invariant T, gd T, and natural killer cell activation. In addition, vaccine-induced B cells were not maintained in peripheral blood at 1 year after vaccination. We provide a dissection of rHA-specific B cells across seven human tissue compartments, showing that influenza-specific memory (CD21hiCD27+) B cells primarily reside within secondary lymphoid tissues and the lungs. Our study suggests that a rational design of universal vaccines needs to consider circulating TFH cells, preexisting serological memory, and tissue compartmentalization for effective B cell immunity, as well as to improve targeting cellular T cell immunity.
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U2 - 10.1126/scitranslmed.aan8405
DO - 10.1126/scitranslmed.aan8405
M3 - Article
C2 - 29444980
AN - SCOPUS:85042110429
SN - 1946-6234
VL - 10
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 428
M1 - eaan8405
ER -