NFKB2 regulates human Tfh and Tfr pool formation and germinal center potential

被引：17

作者：

De Leo, Pasqualina ^{[1
]}

Gazzurelli, Luisa ^{[2
,3
]}

Baronio, Manuela ^{[2
,3
]}

Montin, Davide ^{[4
]}

Di Cesare, Silvia ^{[5
,6
]}

Giancotta, Carmen ^{[5
,6
]}

Licciardi, Francesco ^{[4
]}

Cancrini, Caterina ^{[5
,6
]}

Aiuti, Alessandro ^{[7
,9
]}

Plebani, Alessandro ^{[2
,3
]}

Cicalese, Maria Pia ^{[7
,8
]}

Lougaris, Vassilios ^{[2
,3
]}

Fousteri, Georgia ^{[1
]}

机构：

[1] IRCCS, San Raffaele Sci Inst, DITID, DRI, Milan, Italy

[2] Univ Brescia, Pediat Clin, Dept Clin & Expt Sci, ASST Spedali Civili Brescia, Brescia, Italy

[3] Univ Brescia, Inst Mol Med A Novicelli, ASST Spedali Civili Brescia, Brescia, Italy

[4] Citta Salute & Sci Torino, Dept Paediat 2, Immunorheumatol, Regina Margherita Hosp, Turin, Italy

[5] Childrens Hosp Bambino Gesu, Univ Dept Pediat, Unit Immune & Infect Dis, Rome, Italy

[6] Univ Roma Tor Vergata, Dept Syst Med, Rome, Italy

[7] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy, SR TIGET, Milan, Italy

[8] Ist Sci San Raffaele, Pediat Immunohematol, Milan, Italy

[9] Univ Vita Salute San Raffaele, Milan, Italy

来源：

CLINICAL IMMUNOLOGY | 2020年 / 210卷

关键词：

Common variable immunodeficiency (CVID); Follicular helper T cells (Tfh); Follicular regulatory T cells (Tfr); T regulatory cells (Treg); NFKB2; NF-KAPPA-B; CELL CYTOTOXIC ACTIVITY; NF-KAPPA-B2; MUTATIONS; PATHWAY;

D O I：

10.1016/j.clim.2019.108309

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Mutations affecting the non-canonical pathway of NF-kappa B were recently identified to underlie a form of common variable immunodeficiency strongly associated with autoimmunity. Although intrinsic B-cell abnormalities explain most of the humoral defects of this disease, detailed data on the impact of NFKB2 on follicular helper (Tfh) and regulatory (Tregs) T cells are scarce. Here, we show that Tfh, CXCR5(+), and CXCR5(-) Treg cell subsets were significantly reduced in patients heterozygous for a truncating mutation of NFKB2. Plasma CXCL13 levels were reduced, underlining an important role for NFKB2 in regulating the germinal center (GC) response. Proinflammatory IFN gamma, IL-17 and IL-10 cytokine production by CD4 T cells was lower in the mutated patients, but the production of IL-4 and IL-21 was not altered. Taken together, our findings show that NFKB2 influences the quality and efficiency of human GC reaction, by affecting not only the B cells but also GC-relevant T cell subsets.

引用

页数：5

共 20 条

[1] The two NF-κB activation pathways and their role in innate and adaptive immunity [J].

Bonizzi, G ;

Karin, M .

TRENDS IN IMMUNOLOGY, 2004, 25 (06) :280-288

[2] Nuclear factor (NF)-κB2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses [J].

Caamaño, JH ;

Rizzo, CA ;

Durham, SK ;

Barton, DS ;

Raventós-Suárez, C ;

Snapper, CM ;

Bravo, R .

JOURNAL OF EXPERIMENTAL MEDICINE, 1998, 187 (02) :185-196

[3] Germline Mutations in NFKB2 Implicate the Noncanonical NF-κB Pathway in the Pathogenesis of Common Variable Immunodeficiency [J].

Chen, Karin ;

Coonrod, Emily M. ;

Kumanovics, Attila ;

Franks, Zechariah F. ;

Durtschi, Jacob D. ;

Margraf, Rebecca L. ;

Wu, Wilfred ;

Heikal, Nahla M. ;

Augustine, Nancy H. ;

Ridge, Perry G. ;

Hill, Harry R. ;

Jorde, Lynn B. ;

Weyrich, Andrew S. ;

Zimmerman, Guy A. ;

Gundlapalli, Adi V. ;

Bohnsack, John F. ;

Voelkerding, Karl V. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2013, 93 (05) :812-824

[4] Follicular regulatory T cells control humoral and allergic immunity by restraining early B cell responses [J].

Clement, Rachel L. ;

Daccache, Joe ;

Mohammed, Mostafa T. ;

Diallo, Alos ;

Blazar, Bruce R. ;

Kuchroo, Vijay K. ;

Lovitch, Scott B. ;

Sharpe, Arlene H. ;

Sage, Peter T. .

NATURE IMMUNOLOGY, 2019, 20 (10) :1360-+

[5] The Alternative NF-κB Pathway in Regulatory T Cell Homeostasis and Suppressive Function [J].

Grinberg-Bleyer, Yenkel ;

Caron, Rachel ;

Seeley, John J. ;

De Silva, Nilushi S. ;

Schindler, Christian W. ;

Hayden, Matthew S. ;

Klein, Ulf ;

Ghosh, Sankar .

JOURNAL OF IMMUNOLOGY, 2018, 200 (07) :2362-2371

[6] NF-κB in immunobiology [J].

Hayden, Matthew S. ;

Ghosh, Sankar .

CELL RESEARCH, 2011, 21 (02) :223-244

[7] Regulation of naive T cell function by the NF-κB2 pathway [J].

Ishimaru, Naozumi ;

Kishimoto, Hidehiro ;

Hayashi, Yoshio ;

Sprent, Jonathan .

NATURE IMMUNOLOGY, 2006, 7 (07) :763-772

[8] Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2 [J].

Klemann, Christian ;

Camacho-Ordonez, Nadezhda ;

Yang, Linlin ;

Eskandarian, Zoya ;

Rojas-Restrepo, Jessica L. ;

Frede, Natalie ;

Bulashevska, Alla ;

Heeg, Maximilian ;

Al-Ddafari, Moudjahed Saleh ;

Premm, Julian ;

Seidl, Maximilian ;

Ammann, Sandra ;

Sherkat, Roya ;

Radhakrishnan, Nita ;

Wamatz, Klaus ;

Unger, Susanne ;

Kobbe, Robin ;

Huefner, Anja ;

Leahy, T. Ronan ;

Ip, Winnie ;

Burns, Siobhan O. ;

Fliegauf, Manfred ;

Grimbacher, Bodo .

FRONTIERS IN IMMUNOLOGY, 2019, 10

[9] Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype [J].

Kuehn, Hye Sun ;

Niemela, Julie E. ;

Sreedhara, Karthik ;

Stoddard, Jennifer L. ;

Grossman, Jennifer ;

Wysocki, Christian A. ;

de la Morena, M. Teresa ;

Garofalo, Mary ;

Inlora, Jingga ;

Snyder, Michael P. ;

Lewis, David B. ;

Stratakis, Constantine A. ;

Fleisher, Thomas A. ;

Rosenzweig, Sergio D. .

BLOOD, 2017, 130 (13) :1553-1564

[10] Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100 [J].

Lee, Cindy Eunhee ;

Fulcher, David A. ;

Whittle, Belinda ;

Chand, Rochna ;

Fewings, Nicole ;

Field, Matthew ;

Andrews, Daniel ;

Goodnow, Christopher C. ;

Cook, Matthew C. .

BLOOD, 2014, 124 (19) :2964-2972

← 1 2 →