Circulating TFH cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity

Marios Koutsakos, Adam K. Wheatley, Liyen Loh, E. Bridie Clemens, Sneha Sant, Simone Nüssing, Annette Fox, Amy W. Chung, Karen L. Laurie, Aeron C. Hurt, Steve Rockman, Martha Lappas, Thomas Loudovaris, Stuart I. Mannering, Glen P. Westall, Michael Elliot, Stuart G. Tangye, Linda M. Wakim, Stephen J. Kent, Thi H.O. Nguyen & 1 others Katherine Kedzierska

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Article numbereaan8405
Number of pages15
JournalScience Translational Medicine
Volume10
Issue number428
DOIs
Publication statusPublished - 14 Feb 2018

Cite this

Koutsakos, M., Wheatley, A. K., Loh, L., Clemens, E. B., Sant, S., Nüssing, S., ... Kedzierska, K. (2018). Circulating TFH cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity. Science Translational Medicine, 10(428), [eaan8405]. https://doi.org/10.1126/scitranslmed.aan8405
Koutsakos, Marios ; Wheatley, Adam K. ; Loh, Liyen ; Clemens, E. Bridie ; Sant, Sneha ; Nüssing, Simone ; Fox, Annette ; Chung, Amy W. ; Laurie, Karen L. ; Hurt, Aeron C. ; Rockman, Steve ; Lappas, Martha ; Loudovaris, Thomas ; Mannering, Stuart I. ; Westall, Glen P. ; Elliot, Michael ; Tangye, Stuart G. ; Wakim, Linda M. ; Kent, Stephen J. ; Nguyen, Thi H.O. ; Kedzierska, Katherine. / Circulating TFH cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity. In: Science Translational Medicine. 2018 ; Vol. 10, No. 428.
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title = "Circulating TFH cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity",
abstract = "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.",
author = "Marios Koutsakos and Wheatley, {Adam K.} and Liyen Loh and Clemens, {E. Bridie} and Sneha Sant and Simone N{\"u}ssing and Annette Fox and Chung, {Amy W.} and Laurie, {Karen L.} and Hurt, {Aeron C.} and Steve Rockman and Martha Lappas and Thomas Loudovaris and Mannering, {Stuart I.} and Westall, {Glen P.} and Michael Elliot and Tangye, {Stuart G.} and Wakim, {Linda M.} and Kent, {Stephen J.} and Nguyen, {Thi H.O.} and Katherine Kedzierska",
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Koutsakos, M, Wheatley, AK, Loh, L, Clemens, EB, Sant, S, Nüssing, S, Fox, A, Chung, AW, Laurie, KL, Hurt, AC, Rockman, S, Lappas, M, Loudovaris, T, Mannering, SI, Westall, GP, Elliot, M, Tangye, SG, Wakim, LM, Kent, SJ, Nguyen, THO & Kedzierska, K 2018, 'Circulating TFH cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity' Science Translational Medicine, vol. 10, no. 428, eaan8405. https://doi.org/10.1126/scitranslmed.aan8405

Circulating TFH cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity. / Koutsakos, Marios; Wheatley, Adam K.; Loh, Liyen; Clemens, E. Bridie; Sant, Sneha; Nüssing, Simone; Fox, Annette; Chung, Amy W.; Laurie, Karen L.; Hurt, Aeron C.; Rockman, Steve; Lappas, Martha; Loudovaris, Thomas; Mannering, Stuart I.; Westall, Glen P.; Elliot, Michael; Tangye, Stuart G.; Wakim, Linda M.; Kent, Stephen J.; Nguyen, Thi H.O.; Kedzierska, Katherine.

In: Science Translational Medicine, Vol. 10, No. 428, eaan8405, 14.02.2018.

Research output: Contribution to journalArticleResearchpeer-review

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

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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