Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies

Cindy S. Ma; Natalie Wong; Geetha Rao; Danielle T. Avery; James Torpy; Thomas Hambridge; Jacinta Bustamante; Satoshi Okada; Jennifer L. Stoddard; Elissa K. Deenick; Simon J. Pelham; Kathryn Payne; Stéphanie Boisson-Dupuis; Anne Puel; Masao Kobayashi; Peter D. Arkwright; Sara Sebnem Kilic; Jamila El Baghdadi; Shigeaki Nonoyama; Yoshiyuki Minegishi; Seyed Alireza Mahdaviani; Davood Mansouri; Aziz Bousfiha; Annaliesse K. Blincoe; Martyn A. French; Peter Hsu; Dianne E. Campbell; Michael O. Stormon; Melanie Wong; Stephen Adelstein; Joanne M. Smart; David A. Fulcher; Matthew C. Cook; Tri Giang Phan; Polina Stepensky; Kaan Boztug; Aydan Kansu; Aydan Ikincioʇullari; Ulrich Baumann; Rita Beier; Tony Roscioli; John B. Ziegler; Paul Gray; Capucine Picard; Bodo Grimbacher; Klaus Warnatz; Steven M. Holland; Jean Laurent Casanova; Gulbu Uzel; Stuart G. Tangye

doi:10.1016/j.jaci.2015.05.036

Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies

Cindy S. Ma, Natalie Wong, Geetha Rao, Danielle T. Avery, James Torpy, Thomas Hambridge, Jacinta Bustamante, Satoshi Okada, Jennifer L. Stoddard, Elissa K. Deenick, Simon J. Pelham, Kathryn Payne, Stéphanie Boisson-Dupuis, Anne Puel, Masao Kobayashi, Peter D. Arkwright, Sara Sebnem Kilic, Jamila El Baghdadi, Shigeaki Nonoyama, Yoshiyuki MinegishiSeyed Alireza Mahdaviani, Davood Mansouri, Aziz Bousfiha, Annaliesse K. Blincoe, Martyn A. French, Peter Hsu, Dianne E. Campbell, Michael O. Stormon, Melanie Wong, Stephen Adelstein, Joanne M. Smart, David A. Fulcher, Matthew C. Cook, Tri Giang Phan, Polina Stepensky, Kaan Boztug, Aydan Kansu, Aydan Ikincioʇullari, Ulrich Baumann, Rita Beier, Tony Roscioli, John B. Ziegler, Paul Gray, Capucine Picard, Bodo Grimbacher, Klaus Warnatz, Steven M. Holland, Jean Laurent Casanova, Gulbu Uzel, Stuart G. Tangye^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

176 Citations (Scopus)

Abstract

Background Follicular helper T (T_FH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. T_FH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of T_FH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. Objective We sought to determine the signaling pathways and cellular interactions required for the development and function of T_FH cells in human subjects. Methods Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cT_FH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. Results Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cT_FH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cT_FH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cT_FH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. Conclusion Specific mutations affect the quantity and quality of cT_FH cells, highlighting the need to assess T_FH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain T_FH cell-induced B-cell differentiation. These findings shed new light on T_FH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.

Original language	English
Pages (from-to)	993-1006.e1
Journal	Journal of Allergy and Clinical Immunology
Volume	136
Issue number	4
DOIs	https://doi.org/10.1016/j.jaci.2015.05.036
Publication status	Published - Oct 2015

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10.1016/j.jaci.2015.05.036

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Ma, C. S., Wong, N., Rao, G., Avery, D. T., Torpy, J., Hambridge, T., Bustamante, J., Okada, S., Stoddard, J. L., Deenick, E. K., Pelham, S. J., Payne, K., Boisson-Dupuis, S., Puel, A., Kobayashi, M., Arkwright, P. D., Kilic, S. S., El Baghdadi, J., Nonoyama, S., ... Tangye, S. G. (2015). Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies. Journal of Allergy and Clinical Immunology, 136(4), 993-1006.e1. https://doi.org/10.1016/j.jaci.2015.05.036

@article{f4b618e87403421f986472d085c1accb,

title = "Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies",

abstract = "Background Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. Objective We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. Methods Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. Results Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. Conclusion Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.",

keywords = "Follicular helper T cells, cytokine signaling, humoral immunity, primary immunodeficiencies",

author = "Ma, {Cindy S.} and Natalie Wong and Geetha Rao and Avery, {Danielle T.} and James Torpy and Thomas Hambridge and Jacinta Bustamante and Satoshi Okada and Stoddard, {Jennifer L.} and Deenick, {Elissa K.} and Pelham, {Simon J.} and Kathryn Payne and St{\'e}phanie Boisson-Dupuis and Anne Puel and Masao Kobayashi and Arkwright, {Peter D.} and Kilic, {Sara Sebnem} and {El Baghdadi}, Jamila and Shigeaki Nonoyama and Yoshiyuki Minegishi and Mahdaviani, {Seyed Alireza} and Davood Mansouri and Aziz Bousfiha and Blincoe, {Annaliesse K.} and French, {Martyn A.} and Peter Hsu and Campbell, {Dianne E.} and Stormon, {Michael O.} and Melanie Wong and Stephen Adelstein and Smart, {Joanne M.} and Fulcher, {David A.} and Cook, {Matthew C.} and Phan, {Tri Giang} and Polina Stepensky and Kaan Boztug and Aydan Kansu and Aydan Ikincioʇullari and Ulrich Baumann and Rita Beier and Tony Roscioli and Ziegler, {John B.} and Paul Gray and Capucine Picard and Bodo Grimbacher and Klaus Warnatz and Holland, {Steven M.} and Casanova, {Jean Laurent} and Gulbu Uzel and Tangye, {Stuart G.}",

note = "Publisher Copyright: {\textcopyright} 2015 American Academy of Allergy, Asthma & Immunology.",

year = "2015",

month = oct,

doi = "10.1016/j.jaci.2015.05.036",

language = "English",

volume = "136",

pages = "993--1006.e1",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "4",

}

Ma, CS, Wong, N, Rao, G, Avery, DT, Torpy, J, Hambridge, T, Bustamante, J, Okada, S, Stoddard, JL, Deenick, EK, Pelham, SJ, Payne, K, Boisson-Dupuis, S, Puel, A, Kobayashi, M, Arkwright, PD, Kilic, SS, El Baghdadi, J, Nonoyama, S, Minegishi, Y, Mahdaviani, SA, Mansouri, D, Bousfiha, A, Blincoe, AK, French, MA, Hsu, P, Campbell, DE, Stormon, MO, Wong, M, Adelstein, S, Smart, JM, Fulcher, DA, Cook, MC, Phan, TG, Stepensky, P, Boztug, K, Kansu, A, Ikincioʇullari, A, Baumann, U, Beier, R, Roscioli, T, Ziegler, JB, Gray, P, Picard, C, Grimbacher, B, Warnatz, K, Holland, SM, Casanova, JL, Uzel, G & Tangye, SG 2015, 'Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies', Journal of Allergy and Clinical Immunology, vol. 136, no. 4, pp. 993-1006.e1. https://doi.org/10.1016/j.jaci.2015.05.036

TY - JOUR

T1 - Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies

AU - Ma, Cindy S.

AU - Wong, Natalie

AU - Rao, Geetha

AU - Avery, Danielle T.

AU - Torpy, James

AU - Hambridge, Thomas

AU - Bustamante, Jacinta

AU - Okada, Satoshi

AU - Stoddard, Jennifer L.

AU - Deenick, Elissa K.

AU - Pelham, Simon J.

AU - Payne, Kathryn

AU - Boisson-Dupuis, Stéphanie

AU - Puel, Anne

AU - Kobayashi, Masao

AU - Arkwright, Peter D.

AU - Kilic, Sara Sebnem

AU - El Baghdadi, Jamila

AU - Nonoyama, Shigeaki

AU - Minegishi, Yoshiyuki

AU - Mahdaviani, Seyed Alireza

AU - Mansouri, Davood

AU - Bousfiha, Aziz

AU - Blincoe, Annaliesse K.

AU - French, Martyn A.

AU - Hsu, Peter

AU - Campbell, Dianne E.

AU - Stormon, Michael O.

AU - Wong, Melanie

AU - Adelstein, Stephen

AU - Smart, Joanne M.

AU - Fulcher, David A.

AU - Cook, Matthew C.

AU - Phan, Tri Giang

AU - Stepensky, Polina

AU - Boztug, Kaan

AU - Kansu, Aydan

AU - Ikincioʇullari, Aydan

AU - Baumann, Ulrich

AU - Beier, Rita

AU - Roscioli, Tony

AU - Ziegler, John B.

AU - Gray, Paul

AU - Picard, Capucine

AU - Grimbacher, Bodo

AU - Warnatz, Klaus

AU - Holland, Steven M.

AU - Casanova, Jean Laurent

AU - Uzel, Gulbu

AU - Tangye, Stuart G.

PY - 2015/10

Y1 - 2015/10

N2 - Background Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. Objective We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. Methods Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. Results Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. Conclusion Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.

AB - Background Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. Objective We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. Methods Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. Results Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. Conclusion Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.

KW - Follicular helper T cells

KW - cytokine signaling

KW - humoral immunity

KW - primary immunodeficiencies

UR - http://www.scopus.com/inward/record.url?scp=84943454615&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2015.05.036

DO - 10.1016/j.jaci.2015.05.036

M3 - Article

SN - 0091-6749

VL - 136

SP - 993-1006.e1

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 4

ER -

Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies

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