DiGeorge syndrome is an immunodeficiency characterized by thymic dysplasia resulting in T cell lymphopenia. Most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, such as autoimmune thrombocytopenia. B cells in DiGeorge syndrome show impaired maturation, with low switched-memory B cells and a wide spectrum of antibody deficiencies or dysgammaglobulinemia, presumably due to impaired germinal center responses. We set out to evaluate circulating follicular helper T cells (cTFHs) in DiGeorge syndrome, as markers of T-B interaction in the germinal centers in a cohort of 17 patients with partial DiGeorge and 21 healthy controls of similar age. cTFHs were characterized as CXCR5+CD45RA- CD4+ T cells using flow cytometry. We verify previous findings that the population of memory CD4+ T cells is relatively increased in diGeorge patients, corresponding to low naïve T cells and impaired T cell production in the thymus. The population of CXCR5+ memory CD4+ T cells (cTFHs) was significantly expanded in patients with DiGeorge syndrome, but only healthy controls and not DiGeorge syndrome patients showed gradual increase of CXCR5 expression on cTFHs with age. We did not observe correlation between cTFHs and serum IgG levels or population of switched memory B cells. There was no difference in cTFH numbers between DiGeorge patients with/without thrombocytopenia and with/without allergy. Interestingly, we show strong decline of PD1 expression on cTFHs in the first 5 years of life in DiGeorge patients and healthy controls, and gradual increase of PD1 and ICOS expression on CD4- T cells in healthy controls later in life. Thus, here, we show that patients with DiGeorge syndrome have elevated numbers of cTFHs, which, however, do not correlate with autoimmunity, allergy, or production of immunoglobulins. This relative expansion of cTFH cells may be a result of impaired T cell development in patients with thymic dysplasia.

Center for Chronic Immunodeficiency Medical Center University of Freiburg Faculty of Medicine Freiburg im Breisgau Germany

Department of Immunology 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Prague Czechia

Department of Rehabilitation and Sports Medicine 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Prague Czechia

Zobrazit více v PubMed

DiGeorge AM, Lischner HW, Dacou C, Arey JB. Absence of thymus. Lancet (1967) 1(7504):1387. PubMed

Driscoll DA, Budarf ML, Emanuel BS. A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11. Am J Hum Genet (1992) 50:924–33. PubMed PMC

Gennery AR. Immunological aspects of 22q11.2 deletion syndrome. Cell Mol Life Sci (2012) 69:12–27.10.1007/s00018-011-0842-z PubMed DOI PMC

McLean-Tooke A, Barge D, Spickett GP, Gennery AR. Immunologic defects in 22q11.2 deletion syndrome. J Allergy Clin Immunol (2008) 122:362–7.10.1016/j.jaci.2008.03.033 PubMed DOI

Davies EG. Immunodeficiency in DiGeorge syndrome and options for treating cases with complete athymia. Front Immunol (2013) 4:322.10.3389/fimmu.2013.00322 PubMed DOI PMC

Šedivá A, Bartůňková J, Zachová R, Hrušák O, Kočárek E, Novotná D, et al. Vývoj imunity u syndromu diGeorge. Alergie (2003):1(8).

Jawad AF, McDonald-Mcginn DM, Zackai E, Sullivan KE. Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Pediatr (2001) 139:715–23.10.1067/mpd.2001.118534 PubMed DOI

Ryan AK, Goodship JA, Wilson DI, Philip N, Levy A, Seidel H, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet (1997) 34:798–804.10.1136/jmg.34.10.798 PubMed DOI PMC

Lima K, Abrahamsen TG, Foelling I, Natvig S, Ryder LP, Olaussen RW. Low thymic output in the 22q11.2 deletion syndrome measured by CCR9+CD45RA+ T cell counts and T cell receptor rearrangement excision circles. Clin Exp Immunol (2010) 161:98–107.10.1111/j.1365-2249.2010.04152.x PubMed DOI PMC

Froňková E, Klocperk A, Svaton M, Nováková M, Kotrova M, Kayserova J, et al. The TREC/KREC assay for the diagnosis and monitoring of patients with DiGeorge syndrome. PLoS One (2014) 9:e114514.10.1371/journal.pone.0114514 PubMed DOI PMC

Zemble R, Prak EL, Mcdonald K, Mcdonald-mcginn D, Zackai E, Sullivan K. Secondary immunologic consequences in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin Immunol (2010) 136:409–18.10.1016/j.clim.2010.04.011 PubMed DOI PMC

Patel K, Akhter J, Kobrynski L, Benjamin Gathmann MA, Gathman B, Davis O, et al. Immunoglobulin deficiencies: the B-lymphocyte side of DiGeorge Syndrome. J Pediatr (2012) 161:950–3.10.1016/j.jpeds.2012.06.018 PubMed DOI

Gennery AR, Barge D, O’Sullivan JJ, Flood TJ, Abinun M, Cant AJ. Antibody deficiency and autoimmunity in 22q11.2 deletion syndrome. Arch Dis Child (2002) 86:422–5.10.1136/adc.86.6.422 PubMed DOI PMC

Klocperk A, Mejstříková E, Kayserová J, Kalina T, Šedivá A. Low marginal zone-like B lymphocytes and natural antibodies characterize skewed B-lymphocyte subpopulations in del22q11 DiGeorge patients. Clin Immunol (2015) 161:144–9.10.1016/j.clim.2015.08.013 PubMed DOI

Finocchi A, Di Cesare S, Romiti ML, Capponi C, Rossi P, Carsetti R, et al. Humoral immune responses and CD27+ B cells in children with DiGeorge syndrome (22q11.2 deletion syndrome). Pediatr Allergy Immunol (2006) 17:382–8.10.1111/j.1399-3038.2006.00409.x PubMed DOI

Ma CS, Deenick EK, Batten M, Tangye SG. The origins, function, and regulation of T follicular helper cells. J Exp Med (2012) 209:1241–53.10.1084/jem.20120994 PubMed DOI PMC

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) 192:1545–52.10.1084/jem.192.11.1545 PubMed DOI PMC

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) 13:412–26.10.1038/nri3447 PubMed DOI

Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery 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) 34:108–21.10.1016/j.immuni.2011.01.009 PubMed DOI PMC

Schatorjé EJH, Gemen EFA, Driessen GJA, Leuvenink J, van Hout RWNM, de Vries E. Paediatric reference values for the peripheral T cell compartment. Scand J Immunol (2012) 75:436–44.10.1111/j.1365-3083.2012.02671.x PubMed DOI

Herati RS, Reuter MA, Dolfi DV, Mansfield KD, Aung H, Badwan OZ, et al. Circulating CXCR5+ PD-1+ response predicts influenza vaccine antibody responses in young adults but not elderly adults. J Immunol (2014) 193:3528–37.10.4049/jimmunol.1302503 PubMed DOI PMC

Ma CS. Human T follicular helper cells in primary immunodeficiency: quality just as important as quantity. J Clin Immunol (2016) 36:40–7.10.1007/s10875-016-0257-6 PubMed DOI

Ma CS, Wong N, Rao G, Avery DT, Torpy J, Hambridge T, et al. Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies. J Allergy Clin Immunol (2015) 136(4):993–1006.e1.10.1016/j.jaci.2015.05.036 PubMed DOI PMC

Unger S, Seidl M, van Schouwenburg P, Rakhmanov M, Bulashevska A, Frede N, et al. The TH1 phenotype of follicular helper T cells indicates an IFN-γ-associated immune dysregulation in patients with CD21 low common variable immunodeficiency. J Allergy Clin Immunol (2018) 141(2):730–40.10.1016/j.jaci.2017.04.041 PubMed DOI

Derfalvi B, Maurer K, McDonald McGinn DM, Zackai E, Meng W, Luning Prak ET, et al. B cell development in chromosome 22q11.2 deletion syndrome. Clin Immunol (2016) 163:1–9.10.1016/j.clim.2015.12.004 PubMed DOI

Dorfman DM, Brown JA, Shahsafaei A, Freeman GJ. Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am J Surg Pathol (2006) 30:802–10.10.1097/01.pas.0000209855.28282.ce PubMed DOI PMC

Choi Y, Kageyama R, Eto D. Bcl6 dependent T follicular helper cell differentiation diverges from effector cell differentiation during priming and depends on the gene Icos. Immunity (2011) 34:932–46.10.1016/j.immuni.2011.03.023 PubMed DOI PMC

Bauquet AT, Jin H, Paterson AM, Mitsdoerffer M, Ho I, Sharpe AH, et al. Costimulatory molecule ICOS plays a critical role in the development of TH-17 and follicular T-helper cells by regulating c- Maf expression and IL-21 production. Nat Immunol (2009) 10:167–75.10.1038/ni.1690 PubMed DOI PMC

Bossaller 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) 177:4927–32.10.4049/jimmunol.177.7.4927 PubMed DOI

Boisson B, Wang YD, Bosompem A, Ma CS, Lim A, Kochetkov T, et al. A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR- B cells. J Clin Invest (2013) 123:4781–5.10.1172/JCI71927 PubMed DOI PMC

Cunill V, Clemente A, Lanio N, Barceló C, Andreu V, Pons J, et al. Follicular T cells from smB-common variable immunodeficiency patients are skewed toward a Th1 phenotype. Front Immunol (2017) 8: 174.10.3389/fimmu.2017.00174 PubMed DOI PMC

Choi J-Y, Ho JH, Pasoto SG, Bunin V, Kim ST, Carrasco S, et al. Circulating follicular helper-like t cells in systemic lupus erythematosus: association with disease activity. Arthritis Rheumatol (2015) 67(4):988–99.10.1002/art.39020 PubMed DOI PMC

Szabo K, Papp G, Barath S, Gyimesi E, Szanto A, Zeher M. Follicular helper T cells may play an important role in the severity of primary Sjögren’s syndrome. Clin Immunol (2013) 147:95–104.10.1016/j.clim.2013.02.024 PubMed DOI

Ma J, Zhu C, Ma B, Tian J, Baidoo SE, Mao C, et al. Increased frequency of circulating follicular helper T cells in patients with rheumatoid arthritis. Clin Dev Immunol (2012) 2012:827480.10.1155/2012/827480 PubMed DOI PMC

Junker AK, Driscoll DA. Humoral immunity in DiGeorge syndrome. J Pediatr (1995) 127:231–7.10.1016/S0022-3476(95)70300-4 PubMed DOI

Kubo S, Nakayamada S, Zhao J, Yoshikawa M, Miyazaki Y, Nawata A, et al. Correlation of T follicular helper cells and plasmablasts with the development of organ involvement in patients with IgG4-related disease. Rheumatology (2017) 57(3):514–24.10.1093/rheumatology/kex455 PubMed DOI

Rao DA, Gurish MF, Marshall JL, Slowikowski K, Fonseka CY, Liu Y, et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature (2017) 542:110–4.10.1038/nature20810 PubMed DOI PMC

Ferrando-mart S, Lorente R, Gurbindo D, De Jose MI, Leal M, Muñoz-Fernández MA. Low thymic output, peripheral homeostasis deregulation, and hastened regulatory T cells differentiation in children with 22q11.2 deletion syndrome. J Pediatr (2014) 164:882–9.10.1016/j.jpeds.2013.12.013 PubMed DOI

Shimada Y, Hayashi M, Nagasaka Y, Ohno-Iwashita Y, Inomata M. Age-associated up-regulation of a negative co-stimulatory receptor PD-1 in mouse CD4+T cells. Exp Gerontol (2009) 44:517–22.10.1016/j.exger.2009.05.003 PubMed DOI

Lee KA, Shin KS, Kim GY, Song YC, Bae EA, Kim IK, et al. Characterization of age-associated exhausted CD8+T cells defined by increased expression of Tim-3 and PD-1. Aging Cell (2016) 15:291–300.10.1111/acel.12435 PubMed DOI PMC

Hsu H, Boudova S, Mvula G, Divala TH, Mungwira RG, Harman C, et al. Prolonged PD1 expression on neonatal Vδ2 lymphocytes dampens proinflammatory responses: role of epigenetic regulation. J Immunol (2016) 197(5):1884–92.10.4049/jimmunol.1600284 PubMed DOI PMC

De Roock S, Hoeks SBEA, Meurs L, Steur A, Hoekstra MO, Prakken BJ, et al. Critical role for programmed death 1 signaling and protein kinase B in augmented regulatory T-cell induction in cord blood. J Allergy Clin Immunol (2011) 128(6):1369–71.10.1016/j.jaci.2011.08.006 PubMed DOI

Profound T Lymphocyte and DNA Repair Defect Characterizes Schimke Immuno-Osseous Dysplasia