The CXCR5 T follicular helper cell compartment in children with antibody deficiencies – in search of a prognostic marker of childhood hypogammaglobulinemia

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Aleksandra Szczawinska-Poplonyk
Katarzyna Tapolska-Jozwiak
Husam Samara
Maciej Boruczkowski
Barbara Wieckowska

Keywords

primary immunodeficiency, hypogammaglobulinemia follicular T helper cells, children

Abstract

Background: Novel immunodiagnostic markers are required in order to discriminate between mild hypogammaglobulinemia and severe humoral primary immune deficiencies in children. The efficacy of an antibody response to infections and vaccines is underpinned by T follicular helper (Tfh) cells, activating an immunoglobulin class switch recombination, somatic hyper-mutations, and affinity maturation.


Objective: To determine the formation of the Tfh cells in antibody deficient children and to define their importance as prognostic markers helpful in defining the severity of hypogammaglobulinemia.


Methods: We retrospectively reviewed medical records of 200 children aged from 2 months to 10 years, in whom hypogammaglobulinemia was assessed, from January to December 2019. In all the children studied, a flow cytometric analysis of the Tfh cell compartment was performed.


Results: In young infants aged from 2 to 9 months, the mean relative frequency of the Tfh population was lower than in the control population. Concomitantly, the relative values of Tfh cells, corresponding with the 95th percentile, were below the reference values in all age groups.


Conclusions: A deficiency of Tfh cells in young infants mirrors the immaturity of the humoral immune response, whereas in older children Tfh cells are proposed as a prognostic marker facilitating to distinguish between mild hypogammaglobulinemia and the developing common variable immunodeficiency.

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References

1. Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F, Lipp M, et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med. 2000;192:1545–5. https://doi. org/10.1084/jem.192.11.1545

2. Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med. 2000;192:1553–62. https://doi.org/10.1084/jem.192.11.1553

3. Hale JS, Ahmed R. Memory T follicular helper CD4 T cells. Front Immunol. 2015;6:16. https://doi.org/10.3389/fimmu. 2015.00016

4. Ma CS, Phan TG. Here, there and everywhere: T follicular helper cells on the move. Immunology. 2017;152:382–7. https://doi.org/10.1111/imm.12793

5. Morita R, Schmitt N, Bentebibel S, Ranganathan R, Bourder L, Zurawski G, et al. Human blood CXCR5+CD4+ T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011;34:108–21. https://doi.org/10.1016/j.immuni.2010.12.012

6. Ma CS, Uzel G, Tangye SG. Human T follicular helper cells in primary immunodeficiencies. Curr Opin Pediatr. 2014;26: 720–6. https://doi.org/10.1097/MOP.0000000000000157

7. Schatorje EJH, Gemen EFA, Driessen GJA, Leuvenink J, van Hout RW, de Vries E. Pediatric reference values for the peripheral T cell compartment. Clin Immunol. 2012;75:436– 44. https://doi.org/10.1111/j.1365-3083.2012.02671.x

8. Slifka MK, Amanna I. How advances in immunology provide insight into improving vaccine efficacy. Vaccine. 2014;32: 2948–57. https://doi.org/10.1016/j.vaccine.2014.03.078

9. Linterman MA. Can follicular helper T cells be targeted to improve vaccine efficacy? F1000Research. 2016;5:88. https:// doi.org/10.12688/f1000research.7388.1

10. Jha V, Janoff EN. Complementary role of CD4+ T cells in response to pneumococcal polysaccharide vaccines in humans. Vaccines. 2019;7:18. https://doi.org/10.3390/vaccines7010018

11. Szczawinska-Poplonyk A, Breborowicz A, Samara H, Ossowska L, Dworacki G. Impaired antigen-specific immune response to vaccines in children with antibody production defects. Clin Vaccine Immunol. 2015;22:875–82. https://doi. org/10.1128/CVI.00148-15

12. Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity 2014;41:529–42. https://doi. org/10.1016/j.immuni.2014.10.004

13. Eto D, Lao C, DiToro D, Barnett B, Escobar TC, Kageyama R, et al. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T (Tfh) cell differentiation. PLoS One. 2011;6:e17739. https://doi.org/10.1371/journal.pone.0017739

14. Schmitt N, Liu Y, Bentebibel SE, Mungala I, Bourdery L, Venuprasad K, et al. The cytokine TGF-β co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells. Nat Immunol. 2014;15:856–65. https://doi.org/10.1038/ni.2947

15. Ma CS, Wong N, Rao G, Avery DT, Torpy J, Hambridge T, et al. Monogenic mutations differentially impact the quantity and quality of T follicular helper cells in human primary immunodeficiencies. J Allergy Clin Immunol. 2015;136:993–1006. https://doi.org/10.1016/j.jaci.2015.05.036

16. Ma CS. Human T follicular helper cells in primary immunodeficiency: Quality just as important as quantity. J Clin Immunol. 2016;36:40-7. https://doi.org/10.1007/s10875-016-0257-6

17. Ma CS, Wong N, Rao G, Nguyen A, Avery DT, Payne K, et al. Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets. J Exp Med. 2016;213:1589–608. https://doi. org/10.1084/jem.20151467

18. Thauland TJ, Pellerin L, Ohgami RS, Bacchetta R, Butte MJ. Case study: Mechanism for increased follicular helper T cell development in activated PI3K delta syndrome. Front Immunol. 2019;10:753. https://doi.org/10.3389/fimmu.2019.00753

19. Preite S, Huang B, Cannons JL, McGavern DB, Schwartzberg PL. PI3KD orchestrates T follicular cell differentiation in a con-text dependent manner: Implications for autoimmunity. Front Immunol. 2019;9:3079. https://doi.org/10.3389/fimmu. 2018.03079

20. Gervasi AL, Horton H. Is infant immunity actively suppressed or immature? Virology 2014;2014:1–9. https://doi.org/10.4137/ VRT.S12248

21. Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, et al. International consensus document (ICON): Common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4:38–59. https://doi.org/10.1016/j.jaip.2015.07.025

22. Sanchez LA, Maggadottir SM, Pantell MS, Lugar P, Rundles CC, Sullivan KE, et al. Two sides of the same coin: Pediatric-onset and adult-onset common variable immune deficiency. J Clin Immunol. 2017;37:592–602. https://doi.org/10.1007/ s10875-017-0415-5

23. Liu Y, Hanson S, Gurugama P, Jones A, Clark B, Ibrahim MA. Novel NFKB2 mutation in early-onset CVID. J Clin Immunol. 2014;34:686–90. https://doi.org/10.1007/s10875-014-0064-x

24. Bosaller L, Burger J, Draeger R, Grimbacher B, Knoth R, Plebani A, et al. ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J Immunol. 2006;177:4927–32. https://doi.org/10.4049/jimmunol.177.7.4927

25. Jogdand GM, Mohanty S, Devadas S. Regulators of Tfh cell differentiation. Front Immunol. 2016;7:520. https://doi. org/10.3389/fimmu.2016.00520

26. Coraglia A, Galassi N, Fernadez Romero DS, Juri MC, Felippo M, Malbran A, et al. Common variable immunodeficiency and circulating Tfh. J Immunol Res. 2016;2016:4951587. https://doi.org/10.1155/2016/4951587

27. Tangye SG, Ma CS, Brink R, Deenick EK. The good, the bad and the ugly – TFH cells in human health and disease. Nat Rev Immunol. 2013;13:412–26. https://doi.org/10.1038/nri3447

28. Petersone L, Edner NM, Ovcinnikovs V, Heuts F, Ross EM, Ntavli E, et al. T cell/B cell collaboration and autoimmunity: An intimate relationship. Front Immunol. 2018;9:1941. https:// doi.org/10.3389/fimmu.2018.01941

29. Gensous N, Charrier M, Duluc D, Contin-Bordes C, Truchetet ME, Lazaro E, et al. T follicular helper cells in auto-immune disorders. Front Immunol. 2018;9:1637. https://doi. org/10.3389/fimmu.2018.01637

30. Crotty S. T follicular helper cell biology: A decade of discovery and diseases. Immunity. 2019;50:1132–48. https://doi. org/10.1016/j.immuni.2019.04.011