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

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 4053-4062 ◽  
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.

scholarly journals Regulation of T Cell Responses by Ionic Salt Signals

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2365
Author(s):  
Christina E. Zielinski
Keyword(s):  
T Cells ◽  
T Cell ◽  
Sodium Chloride ◽  
T Cell Responses ◽  
T Helper Cell ◽  
Helper Cell ◽  
T Helper ◽  
Tissue Microenvironment ◽  
Cell Responses ◽  
The Impact

T helper cell responses are tailored to their respective antigens and adapted to their specific tissue microenvironment. While a great proportion of T cells acquire a resident identity, a significant proportion of T cells continue circulating, thus encountering changing microenvironmental signals during immune surveillance. One signal, which has previously been largely overlooked, is sodium chloride. It has been proposed to have potent effects on T cell responses in the context of autoimmune, allergic and infectious tissue inflammation in mouse models and humans. Sodium chloride is stringently regulated in the blood by the kidneys but displays differential deposition patterns in peripheral tissues. Sodium chloride accumulation might furthermore be regulated by dietary intake and thus by intentional behavior. Together, these results make sodium chloride an interesting but still controversial signal for immune modulation. Its downstream cellular activities represent a potential therapeutic target given its effects on T cell cytokine production. In this review article, we provide an overview and critical evaluation of the impact of this ionic signal on T helper cell polarization and T helper cell effector functions. In addition, the impact of sodium chloride from the tissue microenvironment is assessed for human health and disease and for its therapeutic potential.

scholarly journals Loss of HIV-1–specific CD8+ T Cell Proliferation after Acute HIV-1 Infection and Restoration by Vaccine-induced HIV-1–specific CD4+ T Cells

2004 ◽  
Vol 200 (6) ◽  
pp. 701-712 ◽  
Author(s):  
Mathias Lichterfeld ◽  
Daniel E. Kaufmann ◽  
Xu G. Yu ◽  
Stanley K. Mui ◽  
Marylyn M. Addo ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Chronic Infection ◽  
Cell Function ◽  
Acute Infection ◽  
T Helper Cell ◽  
T Helper ◽  
Functional Defect ◽  
Hiv 1

Virus-specific CD8+ T cells are associated with declining viremia in acute human immunodeficiency virus (HIV)1 infection, but do not correlate with control of viremia in chronic infection, suggesting a progressive functional defect not measured by interferon γ assays presently used. Here, we demonstrate that HIV-1–specific CD8+ T cells proliferate rapidly upon encounter with cognate antigen in acute infection, but lose this capacity with ongoing viral replication. This functional defect can be induced in vitro by depletion of CD4+ T cells or addition of interleukin 2–neutralizing antibodies, and can be corrected in chronic infection in vitro by addition of autologous CD4+ T cells isolated during acute infection and in vivo by vaccine-mediated induction of HIV-1–specific CD4+ T helper cell responses. These data demonstrate a loss of HIV-1–specific CD8+ T cell function that not only correlates with progressive infection, but also can be restored in chronic infection by augmentation of HIV-1–specific T helper cell function. This identification of a reversible defect in cell-mediated immunity in chronic HIV-1 infection has important implications for immunotherapeutic interventions.

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

2016 ◽  
Vol 130 (9) ◽  
pp. 733-746 ◽  
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.

scholarly journals Changes in T-helper cell function in human immunodeficiency virus- infected children during didanosine therapy as a measure of antiretroviral activity

Blood ◽  
1992 ◽  
Vol 80 (9) ◽  
pp. 2196-2202 ◽  
Author(s):  
M Clerici ◽  
E Roilides ◽  
KM Butler ◽  
L DePalma ◽  
D Venzon ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Bacterial Infections ◽  
Cell Function ◽  
Interleukin 2 ◽  
T Helper Cell ◽  
Helper Cell ◽  
T Helper ◽  
Asymptomatic Patients ◽  
Immunodeficiency Virus ◽  
P24 Antigen

Abstract Didanosine has shown activity against the human immunodeficiency virus (HIV) in both children and adults. We prospectively assessed T-helper cell (Th) function as determined by in vitro interleukin-2 (IL-2) production in response to a panel of T-cell stimuli in 22 HIV-infected children before and during didanosine therapy and we correlated the incidence of opportunistic and recurrent bacterial infections with changes in p24 antigen and CD4 counts. Didanosine (270, 360, or 540 mg/m2/d) was administered orally for periods ranging from 8 to 40 weeks (mean, 24 weeks). Five of six asymptomatic patients (Centers for Disease Control P-1) compared with 6 of 16 symptomatic (P-2) patients exhibited improved Th function (greater than threefold increase in IL-2 production to at least 2 of the 4 stimuli) during therapy. Of 12 patients without infections during therapy, 9 (75%) showed improvement in Th function, compared with only 2 of 10 patients with infections (P = .03). Notably, the incidence of infections was not correlated with improvements in CD4 count or decreases in p24 antigen. Improvement in Th function during didanosine therapy is correlated with decreased incidence of infections. Assessment of Th function may provide an additional measurement of immunologic response to antiretroviral therapy.

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

2014 ◽  
Vol 20 (12) ◽  
pp. 2321-2329 ◽  
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

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

2005 ◽  
Vol 201 (2) ◽  
pp. 169-171 ◽  
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.

scholarly journals Changes in T-helper cell function in human immunodeficiency virus- infected children during didanosine therapy as a measure of antiretroviral activity

Blood ◽  
1992 ◽  
Vol 80 (9) ◽  
pp. 2196-2202
Author(s):  
M Clerici ◽  
E Roilides ◽  
KM Butler ◽  
L DePalma ◽  
D Venzon ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Bacterial Infections ◽  
Cell Function ◽  
Interleukin 2 ◽  
T Helper Cell ◽  
Helper Cell ◽  
T Helper ◽  
Asymptomatic Patients ◽  
Immunodeficiency Virus ◽  
P24 Antigen

Didanosine has shown activity against the human immunodeficiency virus (HIV) in both children and adults. We prospectively assessed T-helper cell (Th) function as determined by in vitro interleukin-2 (IL-2) production in response to a panel of T-cell stimuli in 22 HIV-infected children before and during didanosine therapy and we correlated the incidence of opportunistic and recurrent bacterial infections with changes in p24 antigen and CD4 counts. Didanosine (270, 360, or 540 mg/m2/d) was administered orally for periods ranging from 8 to 40 weeks (mean, 24 weeks). Five of six asymptomatic patients (Centers for Disease Control P-1) compared with 6 of 16 symptomatic (P-2) patients exhibited improved Th function (greater than threefold increase in IL-2 production to at least 2 of the 4 stimuli) during therapy. Of 12 patients without infections during therapy, 9 (75%) showed improvement in Th function, compared with only 2 of 10 patients with infections (P = .03). Notably, the incidence of infections was not correlated with improvements in CD4 count or decreases in p24 antigen. Improvement in Th function during didanosine therapy is correlated with decreased incidence of infections. Assessment of Th function may provide an additional measurement of immunologic response to antiretroviral therapy.

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

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.

scholarly journals Alteration at a Single Amino Acid Residue in the T Cell Receptor α Chain Complementarity Determining Region 2 Changes the Differentiation of Naive Cd4 T Cells in Response to Antigen from T Helper Cell Type 1 (Th1) to Th2

2000 ◽  
Vol 191 (12) ◽  
pp. 2065-2074 ◽  
Author(s):  
J. Magarian Blander ◽  
Derek B. Sant'Angelo ◽  
Kim Bottomly ◽  
Charles A. Janeway
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
T Helper Cell ◽  
Cell Type ◽  
T Helper ◽  
Helper Cell Type ◽  
Reference Peptide

To study whether changes in the structure of a T cell receptor (TCR) at a single peptide-contacting residue could affect T cell priming with antigenic peptide, we made transgenic mice with a point mutation in the TCR α chain of the D10.G4.1 (D10) TCR and bred them to D10 β chain transgenic mice. The mutation consisted of a leucine to serine substitution at position 51 (L51S), which we had already established contacted the second amino acid of the peptide such that the response to the reference peptide was reduced by ∼100-fold. A mutation in the reference peptide CA134–146 (CA-WT) from the arginine at peptide position 2 to glycine (R2G) restored full response to this altered TCR. When we examined in vitro priming of naive CD4 T cells, we observed that the response to doses of CA-WT that induced T helper cell type 1 (Th1) responses in naive CD4 T cells from mice transgenic for the D10 TCR gave only Th2 responses in naive CD4 T cells derived from the L51S. However, when we primed the same T cells with the R2G peptide, we observed Th1 priming in both D10 and L51S naive CD4 T cells. We conclude from these data that a mutation in the TCR at a key position that contacts major histocompatibility complex–bound peptide is associated with a shift in T cell differentiation from Th1 to Th2.

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