Circulating CXCR5+PD-1+ICOS+ Follicular T Helper Cells Are Increased Close to the Diagnosis of Type 1 Diabetes in Children With Multiple Autoantibodies

Viisanen, Tyyne; Ihantola, Emmi-Leena; Näntö‐Salonen, Kirsti; Hyöty, Heikki; Nurminen, Noora; Selvenius, Jenni; Juutilainen, Auni; Moilanen, Leena; Pihlajamäki, Jussi; Veijola, Riitta; Toppari, Jorma; Knip, Mikael; Ilonen, Jorma; Kinnunen, Tuure

doi:10.2337/db16-0714

Cited by 95 publications

(84 citation statements)

References 38 publications

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“…So far six major autoantibodies have been identified in T1D: islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA), insulin antibodies (IAA), protein tyrosine phosphatase autoantibodies (IA-2A), zinc transporter 8 antibodies (ZnT8A), and the newly identified tetraspanin 7 antibodies (TSPAN7A). 49 The observation of increased Tfh cells in T1D patients was reproducible in several other studies. Indeed, antigen-experienced memory CD4 + T cells in the blood of T1D patients highly expressed CXCR5, PD-1, ICOS and IL-21, possessing the profile of Tfh.…”

Section: The Aberrant Differentiation and Function Of Tfh Cells In T1dsupporting

confidence: 79%

Follicular helper T cells in type 1 diabetes

Shao

Zheng

et al. 2019

The FASEB Journal

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Type 1 diabetes (T1D) is an autoimmune disease caused by the dysfunction of immune system and consequently the destruction of insulin‐producing β cells. In past decades, numerous studies have uncovered that CD4+ T cell subsets are critical in the pathogenesis of T1D, manifesting that type 1 T helper (Th1) and Th17 cells are pathogenic, while regulatory T (Treg) cells and Th2 cells are protective. More recently, the pathogenic role of another subset, follicular helper T (Tfh) cells that essentially regulate germinal center (GC) formation and humoral responses, has also been demonstrated in T1D and many other autoimmune diseases. In this review, we summarize the evidence for the aberrant differentiation and function of Tfh cells in T1D, and also discuss the underlying mechanisms. A better understanding on the pathogenic role of Tfh cells in T1D will inspire the design of potential therapeutic strategies to target this subset in the future.

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Section: The Aberrant Differentiation and Function Of Tfh Cells In T1dsupporting

confidence: 79%

Follicular helper T cells in type 1 diabetes

Shao

Zheng

et al. 2019

The FASEB Journal

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“…Interestingly, recent reports documented that diabetic patients have cellular and molecular indicators of increased presence of circulating TFH cells[27,28]. We (unpublished data) and others[29] also found that these indicators are present in the peripheral blood prior to disease onset in AAb-positive (AAb + ) non-diabetic individuals, suggesting that TFH cells might contribute to AAb pathogenesis and T1D development.…”

Section: T1dsupporting

confidence: 68%

PTPN22 and islet-specific autoimmunity: What have the mouse models taught us?

Galvani

Fousteri

2017

WJD

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An allelic variant of the protein tyrosin phosphatase non-receptor 22 (PTPN22) gene, PTPN22 R620W, constitutes the strongest non-HLA genetic risk factor for the development of type 1 diabetes (T1D). A number of studies using mouse models have addressed how PTPN22 predisposes to T1D. PTPN22 downmodulation, overexpression or expression of the variant gene in genetically manipulated mice has generated controversial results. These discrepancies probably derive from the fact that PTPN22 has differential effects on innate and adaptive immune responses. Moreover, the effects of PTPN22 are dependent on other genetic variables. Here we discuss these findings and try to explain the discrepancies. Exploring the mechanism by which PTPN22 contributes to islet-specific autoimmunity could help us understand its role in T1D pathogenesis and exploit it as a potential therapeutic target to prevent the disease.

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“…We were unable to undertake experiments to determine if isolated ICOS + cmT FH cells enhanced production of IgG1 or IgG2 PcP-specific antibodies by isolated memory B cells in cell cultures. However, the functional effect of ICOS + cmT FH cells has been clearly demonstrated for other antigens [34, 35, 69] and our comprehensive analyses of the relationship between PcP-specific IgG antibody responses and memory B cells or cmT FH cells in HIV seronegative subjects and HIV patients provides compelling evidence that production of PcP-specific IgG antibodies requires expansion of ICOS + cmT FH cells. Also, we did not compare study groups for PcP-specific opsonophagocytic antibodies or maintenance of IgG1 and IgG2 antibodies beyond D28 and determine their relationship with ICOS + cmT FH cells, which should be done in future studies.…”

Section: Discussionmentioning

confidence: 75%

Production of IgG antibodies to pneumococcal polysaccharides is associated with expansion of ICOS+ circulating memory T follicular-helper cells which is impaired by HIV infection

Abudulai¹,

Fernández²,

Corscadden³

et al. 2017

PLoS ONE

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Dysfunction of T follicular-helper (TFH) cells is a possible cause of impaired germinal centre (GC) and IgG antibody responses in individuals with human immunodeficiency virus-1 (HIV-1) infection and might contribute to decreased magnitude and isotype diversification of IgG antibodies to pneumococcal polysaccharides (PcPs). We examined the production of IgG1 and IgG2 antibodies to PcPs 4, 6B, 9V and 14 by enumerating antibody secreting cells (ASCs) at day (D) 7 and determining fold-increase in serum antibody levels at D28 after vaccination with unconjugated PcPs in HIV seronegative subjects (n = 20) and in HIV patients who were receiving antiretroviral therapy (ART) (n = 28) or who were ART-naive (n = 11) and determined their association with ICOS+ and ICOS- circulating memory TFH (cmTFH) cells (CD4+CD45RA-CD27+CXCR5+PD-1+) and short lived plasmablasts (SPBs) at D7, and with PcP-specific and total IgM+ and IgG+ memory B cells at D0. In HIV seronegative subjects, production of IgG1+ and IgG2+ ASCs was consistently associated with the frequency of ICOS+ cmTFH cells but not ICOS- cmTFH cells or memory B cells. In contrast, post-vaccination ASCs in HIV patients, regardless of ART status, were lower than in HIV seronegative subjects and not associated with ICOS+ cmTFH cells, the expansion of which was absent (ART-naive patients) or much lower than in HIV seronegative subjects (ART-treated patients). Production of SPBs was also lower in ART-naive patients. Fold-increase in IgG2 antibodies at D28 also correlated with ICOS+ cmTFH cells at D7 in HIV seronegative subjects but not in HIV patients. These novel findings provide evidence that ICOS+ cmTFH cells contribute to the regulation of PcP-specific IgG antibody responses, including isotype diversification, and that TFH cell dysfunction may be a cause of impaired PcP-specific IgG antibody responses and increased susceptibility to pneumococcal disease in HIV patients.

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Circulating CXCR5+PD-1+ICOS+ Follicular T Helper Cells Are Increased Close to the Diagnosis of Type 1 Diabetes in Children With Multiple Autoantibodies

Cited by 95 publications

References 38 publications

Follicular helper T cells in type 1 diabetes

Follicular helper T cells in type 1 diabetes

PTPN22 and islet-specific autoimmunity: What have the mouse models taught us?

Production of IgG antibodies to pneumococcal polysaccharides is associated with expansion of ICOS+ circulating memory T follicular-helper cells which is impaired by HIV infection

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