Clearance of chronic HCV infection leads to an expansion of a follicular T helper cell memory phenotype in HCV-specific CD4 T cells

ABSTRACT Vigorous virus-specific CD4+ T-helper-cell responses are associated with successful control of hepatitis C virus (HCV) and other human viral infections, but the breadth and specificity of responses associated with viral containment have not been defined. To address this we evaluated the HCV-specific CD4+ T-helper-cell response in HCV antibody-positive persons who lack detectable plasma viremia, and compared this response to that in persons with chronic HCV infection. Peripheral blood mononuclear cells were stimulated with HCV proteins, followed by measurement of HCV-specific CD4+-T-cell responses to a comprehensive set of overlapping HCV peptides by intracellular gamma interferon production. In three persons with resolved HCV infection studied in detail, 13 to 14 epitopes were targeted, but none was recognized by all three. The 37 defined epitopes were predominantly distributed among the HCV proteins core, NS3, NS4, and NS5. In an expanded analysis of responses to these proteins in persons with resolved infection, an average of 10 epitopes was targeted, whereas in persons with chronic viremia never was more than one epitope targeted (P < 0.001). This comprehensive analysis of the breadth and specificity of HCV-specific T-helper-cell responses indicates that up to 14 viral epitopes can be simultaneously targeted by circulating virus-specific CD4+ T helper cells in a controlled human viral infection. Moreover, these data provide important parameters for evaluation of candidate HCV vaccines, and provide rationale for immunotherapy in chronic HCV infection.

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CD154 expression reveals the presence of dysfunctional virus-specific CD4+ T cells during chronic HCV infection

Zeitschrift für Gastroenterologie ◽

10.1055/s-2008-1037612 ◽

2008 ◽

Vol 46 (01) ◽

Author(s):

N Semmo ◽

M Müller ◽

C Neumann-Haefelin ◽

HC Spangenberg ◽

HE Blum ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Hcv Infection ◽

Chronic Hcv Infection ◽

Chronic Hcv

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Defective T-helper cell function after T-cell–depleting therapy affecting naive and memory populations

Blood ◽

10.1182/blood.v99.11.4053 ◽

2002 ◽

Vol 99 (11) ◽

pp. 4053-4062 ◽

Cited By ~ 23

Author(s):

Andreas Heitger ◽

Patricia Winklehner ◽

Petra Obexer ◽

Johannes Eder ◽

Claudia Zelle-Rieser ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Mononuclear Cells ◽

Cell Function ◽

Interleukin 2 ◽

T Helper Cell ◽

Helper Cell ◽

High Dose ◽

T Helper

Impaired T-cell function after T-cell– depleting (TCD) therapy has been hypothesized to be related to a transient predominance of extrathymically expanding memory T cells. To test whether after TCD therapy the naive T-helper cell population is functionally intact, the in vitro immune response of CD4+CD45RA+ (naive) and of CD4+CD45RA− (memory) cells to polyclonal mitogens (immobilized anti-CD3, phytohemagglutinin) was analyzed by flow cytometry in 22 pediatric patients after high-dose chemotherapy (including 5 after autologous and 5 after allogeneic stem cell support). At 1 to 3 months after TCD therapy, patient samples showing decreased lymphoproliferative responses also showed a reduced induction of the early activation marker CD69 by CD4+ T cells from 4 to 72 hours after stimulation even when supplemented with exogenous interleukin-2. This defect affected CD4+CD45RA− cells, but, strikingly, also CD4+CD45RA+ cells, including samples in which CD4+CD45RA+ cells were more than 90/μL, thus indicating ongoing thymopoiesis. Histogram analyses showed the median peak channel of CD69 in control CD4+CD45RA+cells rising 98-fold (median) but only 28-fold in patient cells (P < .0001). Apoptosis as detected by annexin V staining was increased in resting patient CD4+ T cells (25% versus 6%) and also affected CD4+CD45RA+ cells (12% versus 5%, P < .01). When peripheral blood mononuclear cells (PBMCs) were enriched for T cells, stimulatory responses of CD4+ cells and of CD4+CD45RA+ cells markedly improved. Thus, after TCD therapy suppressor factors contained in the non–T-cell fraction of PBMCs may affect T-helper cells irrespective of their naive or memory phenotype thus extending T-cell dysfunction to the presumably thymus-dependently regenerated T cells.

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Aberrantly methylated DNA regions lead to low activation of CD4+ T-cells in IgA nephropathy

Clinical Science ◽

10.1042/cs20150711 ◽

2016 ◽

Vol 130 (9) ◽

pp. 733-746 ◽

Cited By ~ 10

Author(s):

Fabio Sallustio ◽

Grazia Serino ◽

Sharon N. Cox ◽

Alessandra Dalla Gassa ◽

Claudia Curci ◽

...

Keyword(s):

T Cells ◽

Iga Nephropathy ◽

Cd4 T Cells ◽

Signal Strength ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Methylated Dna

DNA regions abnormally methylated in IgAN patients led to the reduced TCR signal strength of CD4+ T-cells and to their anomalous response, explaining the T-helper cell imbalance.

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Comprehensive Intestinal T Helper Cell Profiling Reveals Specific Accumulation of IFN-γ+IL-17+Coproducing CD4+ T Cells in Active Inflammatory Bowel Disease

Inflammatory Bowel Diseases ◽

10.1097/mib.0000000000000210 ◽

2014 ◽

Vol 20 (12) ◽

pp. 2321-2329 ◽

Cited By ~ 71

Author(s):

Anna-Maria Globig ◽

Nadine Hennecke ◽

Bianca Martin ◽

Maximilian Seidl ◽

Günther Ruf ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

Bowel Disease ◽

Cd4 T Cells ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Specific Accumulation ◽

Inflammatory Bowel ◽

Ifn Γ

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IL-12– and IL-23–induced T helper cell subsets

Journal of Experimental Medicine ◽

10.1084/jem.20042279 ◽

2005 ◽

Vol 201 (2) ◽

pp. 169-171 ◽

Cited By ~ 105

Author(s):

Estelle Bettelli ◽

Vijay K. Kuchroo

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Th Cells ◽

Th 1

Traditionally, CD4+ T cells have been separated into two different subsets named T helper (Th)1 and Th2. A new IL-23–driven subset of Th cells called ThIL-17 has now been described. The data suggest that IL-23 plays an important role in the differentiation of autoreactive pathogenic T cells. Whether these IL-23–induced ThIL-17 cells are a unique subset or are related to other Th subsets is discussed.

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Intrahepatic HCV-Specific CD4+ T cells in chronic HCV-infection are multispecific and produce γ-IFN

Journal of Hepatology ◽

10.1016/s0168-8278(00)80461-4 ◽

2000 ◽

Vol 32 ◽

pp. 33

Author(s):

C.A. Schirren ◽

M.C. Jung ◽

T. Worzfeld ◽

J.T. Gerlach ◽

N.H. Gruener ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Hcv Infection ◽

Chronic Hcv Infection ◽

Chronic Hcv

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IL-17+ mast cell/T helper cell axis in the early stages of acne

10.1101/2021.06.29.450328 ◽

2021 ◽

Author(s):

Yoan Eliasse ◽

Edouard leveque ◽

Louise Battut ◽

Thérèse Nocera ◽

Lucile Garidou ◽

...

Keyword(s):

T Cells ◽

Mast Cell ◽

Mast Cells ◽

Cd4 T Cells ◽

Immune Cell ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Cell Axis ◽

Early Stages

Acne is a multifactorial disease driven by physiological changes occurring during puberty in the pilosebaceous unit (PSU) that leads to sebum overproduction and a dysbiosis involving notably Cutibacterium acnes. These changes in the PSU microenvironment lead to a shift from a homeostatic to an inflammatory state. Indeed, immunohistochemical analyses have revealed that inflammation and lymphocyte infiltration can be detected even in the infraclinical acneic stages, highlighting the importance of the early stages of the disease. In this study, we utilized a robust multi-pronged approach that included flow cytometry, confocal microscopy, and bioinformatics to comprehensively characterize the evolution of the infiltrating and resident immune cell populations in acneic lesions, beginning in the early stages of their development. Using a discovery cohort of 15 patients, we demonstrated that the composition of immune cell infiltrate is highly dynamic in nature, with the relative abundance of different cell types changing significantly as a function of clinical lesion stage. Within the stages examined, we identified a large population of CD69+ CD4+ T cells, several populations of activated antigen presenting cells, and activated mast cells producing IL-17. IL-17+ mast cells were preferentially located in CD4+ T cell rich areas and we showed that activated CD4+ T cells license mast cells to produce IL-17. Our study reveals that mast cells are the main IL-17 producers in the early stage of acne, underlying the importance of targeting the IL-17+ mast cell/T helper cell axis in therapeutic approaches.

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Age-Related Dynamics of Circulating Innate Lymphoid Cells in an African Population

Frontiers in Immunology ◽

10.3389/fimmu.2020.594107 ◽

2020 ◽

Vol 11 ◽

Author(s):

Alansana Darboe ◽

Carolyn M. Nielsen ◽

Asia-Sophia Wolf ◽

Jacob Wildfire ◽

Ebrima Danso ◽

...

Keyword(s):

T Cells ◽

Life Course ◽

Peripheral Blood ◽

Cd4 T Cells ◽

T Helper Cell ◽

Helper Cell ◽

Effector Memory ◽

T Helper ◽

Age Related ◽

The Life Course

Innate lymphoid cell (ILC) lineages mirror those of CD4+ T helper cell subsets, producing type 1, 2 and 3 cytokines respectively. Studies in adult human populations have shown contributions of non-cytotoxic ILC to immune regulation or pathogenesis in a wide range of diseases and have prompted investigations of potential functional redundancy between ILC and T helper cell compartments in neonates and children. To investigate the potential for ILC to contribute to immune responses across the human lifespan, we examined the numbers and frequencies of peripheral blood ILC subsets in a cohort of Gambians aged between 5 and 73 years of age. ILC2 were the most abundant peripheral blood ILC subset in this Gambian cohort, while ILC1 were the rarest at all ages. Moreover, the frequency of ILC1s (as a proportion of all lymphocytes) was remarkably stable over the life course whereas ILC3 cell frequencies and absolute numbers declined steadily across the life course and ILC2 frequencies and absolute numbers declined from childhood until the age of approx. 30 years of age. Age-related reductions in ILC2 cell numbers appeared to be partially offset by increasing numbers of total and GATA3+ central memory (CD45RA-CCR7+) CD4+ T cells, although there was also a gradual decline in numbers of total and GATA3+ effector memory (CD45RA-CCR7-) CD4+ T cells. Despite reduced overall abundance of ILC2 cells, we observed a coincident increase in the proportion of CD117+ ILC2, indicating potential for age-related adaptation of these cells in childhood and early adulthood. While both CD117+ and CD117- ILC2 cells produced IL-13, these responses occurred predominantly within CD117- cells. Furthermore, comparison of ILC frequencies between aged-matched Gambian and UK young adults (25–29 years) revealed an overall higher proportion of ILC1 and ILC2, but not ILC3 in Gambians. Thus, these data indicate ongoing age-related changes in ILC2 cells throughout life, which retain the capacity to differentiate into potent type 2 cytokine producing cells, consistent with an ongoing role in immune modulation.

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