The cAMP responsive element modulator (CREM) is a regulator of CD4+ T cell function

Abstract The cAMP responsive element modulator (CREM) is a transcriptional regulator of different effector cytokines in CD4+ T cells including IL-2, IL-17, IL-21 but also IL-4 and IL-13 and thus an important determinant of central T helper cell functions. Our review gives an overview over the regulation of CREM in T cells and the pleiotropic effects of CREM on CD4+ T cells in health and autoimmune diseases with a particular focus on systemic lupus erythematosus.

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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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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

Journal of Experimental Medicine ◽

10.1084/jem.20041270 ◽

2004 ◽

Vol 200 (6) ◽

pp. 701-712 ◽

Cited By ~ 267

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.

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Depressed primary in vitro antibody response in untreated systemic lupus erythematosus. T helper cell defect and lack of defective suppressor cell function.

Journal of Clinical Investigation ◽

10.1172/jci109827 ◽

1980 ◽

Vol 66 (1) ◽

pp. 141-148 ◽

Cited By ~ 44

Author(s):

J F Delfraissy ◽

P Segond ◽

P Galanaud ◽

C Wallon ◽

P Massias ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Antibody Response ◽

Lupus Erythematosus ◽

Cell Function ◽

Suppressor Cell ◽

T Helper Cell ◽

T Helper ◽

Systemic Lupus ◽

Cell Defect

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Human interleukin 17–producing cells originate from a CD161+CD4+ T cell precursor

Journal of Experimental Medicine ◽

10.1084/jem.20080397 ◽

2008 ◽

Vol 205 (8) ◽

pp. 1903-1916 ◽

Cited By ~ 497

Author(s):

Lorenzo Cosmi ◽

Raffaele De Palma ◽

Veronica Santarlasci ◽

Laura Maggi ◽

Manuela Capone ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Natural Killer T Cells ◽

T Helper Cell ◽

Cd4 T Cell ◽

Interleukin 17 ◽

T Helper ◽

Cell Precursor ◽

Killer T Cells

We demonstrate that CD161 is a highly up-regulated gene in human interleukin (IL) 17 T helper cell (Th17) clones and that all IL-17–producing cells are contained in the CD161+ fraction of CD4+ T cells present in the circulation or in inflamed tissues, although they are not CD1-restricted natural killer T cells. More importantly, we show that all IL-17–producing cells originate from CD161+ naive CD4+ T cells of umbilical cord blood, as well as of the postnatal thymus, in response to the combined activity of IL-1β and IL-23. These findings implicate CD161 as a novel surface marker for human Th17 cells and demonstrate the exclusive origin of these cells from a CD161+CD4+ T cell progenitor.

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Mice from a genetically resistant background lacking the interferon γ receptor are susceptible to infection with Leishmania major but mount a polarized T helper cell 1-type CD4+ T cell response.

Journal of Experimental Medicine ◽

10.1084/jem.181.3.961 ◽

1995 ◽

Vol 181 (3) ◽

pp. 961-971 ◽

Cited By ~ 155

Author(s):

K Swihart ◽

U Fruth ◽

N Messmer ◽

K Hug ◽

R Behin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Leishmania Major ◽

T Helper Cell ◽

Cd4 T Cell ◽

Helper Cell ◽

Wild Type ◽

T Helper ◽

Ifn Gamma ◽

Gamma Receptor

Mice with homologous disruption of the gene coding for the ligand-binding chain of the interferon (IFN) gamma receptor and derived from a strain genetically resistant to infection with Leishmania major have been used to study further the role of this cytokine in the differentiation of functional CD4+ T cell subsets in vivo and resistance to infection. Wild-type 129/Sv/Ev mice are resistant to infection with this parasite, developing only small lesions, which resolve spontaneously within 6 wk. In contrast, mice lacking the IFN-gamma receptor develop large, progressing lesions. After infection, lymph nodes (LN) and spleens from both wild-type and knockout mice showed an expansion of CD4+ cells producing IFN-gamma as revealed by measuring IFN-gamma in supernatants of specifically stimulated CD4+ T cells, by enumerating IFN-gamma-producing T cells, and by Northern blot analysis of IFN-gamma transcripts. No biologically active interleukin (IL) 4 was detected in supernatants of in vitro-stimulated LN or spleen cells from infected wild-type or deficient mice. Reverse transcription polymerase chain reaction analysis with primers specific for IL-4 showed similar IL-4 message levels in LN from both types of mice. The IL-4 message levels observed were comparable to those found in similarly infected C57BL/6 mice and significantly lower than the levels found in BALB/c mice. Anti-IFN-gamma treatment of both types of mice failed to alter the pattern of cytokines produced after infection. These data show that even in the absence of IFN-gamma receptors, T helper cell (Th) 1-type responses still develop in genetically resistant mice with no evidence for the expansion of Th2 cells.

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Functional heterogeneity of L3T4+ T cells in MRL-lpr/lpr mice. L3T4+ T cells suppress major histocompatibility complex-self-restricted L3T4+ T helper cell function in association with autoimmunity.

Journal of Experimental Medicine ◽

10.1084/jem.168.6.2165 ◽

1988 ◽

Vol 168 (6) ◽

pp. 2165-2181 ◽

Cited By ~ 23

Author(s):

C S Via ◽

G M Shearer

Keyword(s):

T Cells ◽

Lupus Erythematosus ◽

Cell Function ◽

Suppressor Cells ◽

Functional Specialization ◽

Compensatory Mechanism ◽

T Helper ◽

Spleen Cells ◽

Histocompatibility Complex ◽

Age Dependent

The present study demonstrates in MRl-lpr/lpr autoimmune mice an age-dependent loss of MHC-self-restricted function by L3T4+ Th. This defect is not present in age-matched, congenic MRL-+/+ spleen cells and appears to be due to the presence of suppressor cells that are selective for L3T4+ Th and not for Lyt-2+ Th. Surprisingly, the suppressor cells are also L3T4+ T cells and can suppress the IL-2 production of congenic MRL/+ L3T4+ Th to MHC-self-restricted antigens. These data support the idea of functional specialization within the L3T4+ population of T cells. Because L3T4+ suppressor cells are detected late in the course of autoimmunity, we interpret their presence not as a primary initiating event in the development of autoimmunity, but rather as a compensatory mechanism. Additionally, similar suppression of L3T4+ Th function has also been reported in a murine graft-vs.-host model of autoimmunity, suggesting that the suppressor cells represent an immunoregulatory mechanism that is a common feature of autoimmunity. Since excessive class II-restricted Th activity for B cells has been reported for both models of autoimmunity, L3T4+ suppressor cells may represent an attempt to down regulate such excessive Th activity. These findings may be relevant to human autoimmune diseases, such as systemic lupus erythematosus, in which B cell hyperactivity is also associated with reduced IL-2 production by Th.

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Expansion of HCV-specific T cells with a follicular T helper cell phenotype after DAA mediated antigen removal

Zeitschrift für Gastroenterologie ◽

10.1055/s-0037-1612883 ◽

2018 ◽

Vol 56 (01) ◽

pp. E2-E89

Author(s):

M Smits ◽

C Fauvelle ◽

T Baumert ◽

C Neumann-Haefelin ◽

R Thimme ◽

...

Keyword(s):

T Cells ◽

T Helper Cell ◽

Helper Cell ◽

Cell Phenotype ◽

T Helper ◽

Antigen Removal

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Generation of IL-8 and IL-9 Producing CD4+T Cells Is Affected by Th17 Polarizing Conditions and AHR Ligands

Mediators of Inflammation ◽

10.1155/2014/182549 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 13

Author(s):

Michaela Gasch ◽

Tina Goroll ◽

Mario Bauer ◽

Denise Hinz ◽

Nicole Schütze ◽

...

Keyword(s):

T Cells ◽

T Helper Cells ◽

Th17 Cells ◽

Immune Cell ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Helper Cells ◽

Aryl Hydrocarbon

The T helper cell subsets Th1, Th2, Th17, and Treg play an important role in immune cell homeostasis, in host defense, and in immunological disorders. Recently, much attention has been paid to Th17 cells which seem to play an important role in the early phase of the adoptive immune response and autoimmune disease. When generating Th17 cells underin vitroconditions the amount of IL-17A producing cells hardly exceeds 20% while the nature of the remaining T cells is poorly characterized. As engagement of the aryl hydrocarbon receptor (AHR) has also been postulated to modulate the differentiation of T helper cells into Th17 cells with regard to the IL-17A expression we ask how far do Th17 polarizing conditions in combination with ligand induced AHR activation have an effect on the production of other T helper cell cytokines. We found that a high proportion of T helper cells cultured under Th17 polarizing conditions are IL-8 and IL-9 single producing cells and that AHR activation results in an upregulation of IL-8 and a downregulation of IL-9 production. Thus, we have identified IL-8 and IL-9 producing T helper cells which are subject to regulation by the engagement of the AHR.

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