Diminished Production of T Helper 1 Cytokines and Lack of Induction of IL-2R+T Cells Correlate with T-Cell Unresponsiveness in Rhesus Monkeys Chronically Infected withBrugia malayi

1998 ◽  
Vol 90 (1) ◽  
pp. 77-85 ◽  
Author(s):  
Guillermo H. Giambartolomei ◽  
Barbara L. Lasater ◽  
François Villinger ◽  
Vida A. Dennis
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rhesus Monkeys ◽  
T Helper ◽  
T Helper 1

scholarly journals CD4+T Cells: Differentiation and Functions

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Rishi Vishal Luckheeram ◽  
Rui Zhou ◽  
Asha Devi Verma ◽  
Bing Xia
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Cytokine Signaling ◽  
T Helper ◽  
T Helper 1 ◽  
T Helper 17 ◽  
Differentiated Cells ◽  
Follicular Helper ◽  
Follicular Helper T Cell

CD4+T cells are crucial in achieving a regulated effective immune response to pathogens. Naive CD4+T cells are activated after interaction with antigen-MHC complex and differentiate into specific subtypes depending mainly on the cytokine milieu of the microenvironment. Besides the classical T-helper 1 and T-helper 2, other subsets have been identified, including T-helper 17, regulatory T cell, follicular helper T cell, and T-helper 9, each with a characteristic cytokine profile. For a particular phenotype to be differentiated, a set of cytokine signaling pathways coupled with activation of lineage-specific transcription factors and epigenetic modifications at appropriate genes are required. The effector functions of these cells are mediated by the cytokines secreted by the differentiated cells. This paper will focus on the cytokine-signaling and the network of transcription factors responsible for the differentiation of naive CD4+T cells.

scholarly journals Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice

2016 ◽  
Vol 91 (5) ◽  
Author(s):  
Junghwa Lee ◽  
Masao Hashimoto ◽  
Se Jin Im ◽  
Koichi Araki ◽  
Hyun-Tak Jin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
T Helper ◽  
T Helper 1 ◽  
Cell Responses ◽  
Serotype 5 ◽  
Lcmv Infection

ABSTRACT Adenovirus serotype 5 (Ad5) is one of the most widely used viral vectors and is known to generate potent T cell responses. While many previous studies have characterized Ad5-induced CD8 T cell responses, there is a relative lack of detailed studies that have analyzed CD4 T cells elicited by Ad5 vaccination. Here, we immunized mice with Ad5 vectors encoding lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) and examined GP-specific CD4 T cell responses elicited by Ad5 vectors and compared them to those induced by an acute LCMV infection. In contrast to LCMV infection, where balanced CD4 T helper 1 (Th1) and T follicular helper (Tfh) responses were induced, Ad5 immunization resulted in a significantly reduced frequency of Th1 cells. CD4 T cells elicited by Ad5 vectors expressed decreased levels of Th1 markers, such as Tim3, SLAM, T-bet, and Ly6C, had smaller amounts of cytotoxic molecules like granzyme B, and produced less interferon gamma than CD4 T cells induced by LCMV infection. This defective CD4 Th1 response appeared to be intrinsic for Ad5 vectors and not a reflection of comparing a nonreplicating vector to a live viral infection, since immunization with a DNA vector expressing LCMV-GP generated efficient CD4 Th1 responses. Analysis at early time points (day 3 or 4) after immunization with Ad5 vectors revealed a defect in the expression of CD25 (interleukin-2 [IL-2] receptor alpha chain) on Ad5-elicited CD4 T cells, and administration of exogenous IL-2 following Ad5 immunization partially restored CD4 Th1 responses. These results suggest that impairment of Th1 commitment after Ad5 immunization could be due to reduced IL-2-mediated signaling. IMPORTANCE During viral infection, generating balanced responses of Th1 and Tfh cells is important to induce effective cell-mediated responses and provide optimal help for antibody responses. In this study, to investigate vaccine-induced CD4 T cell responses, we characterized CD4 T cells after immunization with Ad5 vectors expressing LCMV-GP in mice. Ad5 vectors led to altered effector differentiation of LCMV GP-specific CD4 T cells compared to that during LCMV infection. CD4 T cells following Ad5 immunization exhibited impaired Th1 lineage commitment, generating significantly decreased Th1 responses than those induced by LCMV infection. Our results suggest that suboptimal IL-2 signaling possibly plays a role in reduced Th1 development following Ad5 immunization.

scholarly journals T-cell response to bacterial agents

2011 ◽  
Vol 5 (09) ◽  
pp. 640-645 ◽  
Author(s):  
Mario Milco D'Elios ◽  
Marisa Benagiano ◽  
Chiara Della Bella ◽  
Amedeo Amedei
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Th2 Cells ◽  
T Helper ◽  
T Helper 1 ◽  
Cell Responses ◽  
Genetic And Environmental Factors ◽  
Bacteria And Fungi ◽  
Antigen Presenting

T-cell responses are crucial for the outcome of any infection. The type of effector T-cell reaction is determined by a complex interaction of antigen-presenting cells with naive T cells and involves genetic and environmental factors, including the type of antigen, cytokines, chemokines, co-stimulatory molecules, and signalling cascades. The decision for the immune response to go in a certain direction is based not on one signal alone, but rather on many different elements acting both synergistically and antagonistically, and through feedback loops leading to activation or inhibition of T cells. In the course of evolution different types of T cells have developed, such as T helper 1 (Th1) cells, which protect against intracellular bacteria; Th2 cells, which play a role against parasites; and Th17 cells, which face extracellular bacteria and fungi

Mechanisms of anti-viral Cytotoxic CD4 T cell differentiation

2021 ◽  
Author(s):  
Cory J. Knudson ◽  
Maria Férez ◽  
Pedro Alves-Peixoto ◽  
Dan A. Erkes ◽  
Carolina R. Melo-Silva ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Viral Infection ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Transcriptional Analysis ◽  
Th1 Cells ◽  
T Helper ◽  
T Helper 1

Cytotoxic CD4 T lymphocytes (CD4-CTL) are important in anti-viral immunity. For example, we have previously shown that in mice, CD4-CTL are important to control ectromelia virus (ECTV) infection. How viral infections induce CD4-CTL responses remains incompletely understood. Here we demonstrate that not only ECTV but also vaccinia virus and Lymphocytic Choriomeningitis virus induce CD4-CTL, but that the response to ECTV is stronger. Using ECTV, we also demonstrate that in contrast to CD8-CTL, CD4-CTL differentiation requires constant virus replication and ceases once the virus is controlled. We also show that Major Histocompatibility Complex Class II molecules on CD11c + cells are required for CD4-CTL differentiation and for mousepox resistance. Transcriptional analysis indicated that anti-viral CD4-CTL and non-cytolytic T Helper 1 (Th1) CD4 T cells have similar transcriptional profiles, suggesting that CD4-CTL are terminally differentiated classical Th1 cells. Interestingly, CD4-CTL and classical Th1 cells expressed similar mRNA levels of the transcription factors ThPOK and GATA-3, necessary for CD4 T cell linage commitment; and Runx3, required for CD8 T cell development and effector function. However, at the protein level, CD4-CTL had higher levels of the three transcription factors suggesting that further post-transcriptional regulation is required for CD4-CTL differentiation. Finally, using CRISPR-Cas9 deletion of Runx3 in CD4 T cells, we demonstrate that the development of CD4-CTL but not of classical Th1 CD4 T cells requires Runx3 following ECTV infection. These results further our understanding of the mechanisms of CD4-CTL differentiation during viral infection and the role of post-transcriptionally regulated Runx3 in this process. IMPORTANCE While it is well established that cytotoxic CD4 T cells (CD4-CTL) directly contribute to viral clearance, it remains unclear how CD4-CTL are induced. We now show that CD4-CTL require sustained antigen presentation and are induced by CD11c-expressing antigen presenting cells. Moreover, we show that CD4-CTL are derived from the terminal differentiation of classical T helper 1 (Th1) subset of CD4 cells. Compared to Th1 cells, CD4-CTL upregulate protein levels of the transcription factors ThPOK, Runx3 and GATA-3 post-transcriptionally. Deletion of Runx3 in differentiated CD4 T cells prevents CD4-CTL but not of classical Th1 cells. These results advance our knowledge of how CD4-CTL are induced during viral infection.

Severe immune-related adverse events in anti-PD-1-treated patients are clustered into distinct subtypes by peripheral blood T-cell profiles.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2564-2564
Author(s):  
Kyung Hwan Kim ◽  
Jinhyun Cho ◽  
Joon Young Hur ◽  
Bo Mi Ku ◽  
Jiae Koh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adverse Events ◽  
Peripheral Blood ◽  
Clinical Manifestations ◽  
T Helper ◽  
T Helper 1 ◽  
Ki 67 ◽  
Epithelial Tumor ◽  
Color Flow

2564 Background: Although anti-programmed death-1 (PD-1) treatment has shown remarkable anti-tumor efficacy, immune-related adverse events (irAEs) develop with heterogeneous clinical manifestations. Immunological understanding of irAEs is currently limited. In the present study, we analyzed peripheral blood T cells obtained from cancer patients who received anti-PD-1 treatment to determine the immunological characteristics of severe irAEs. Methods: This study included 31 patients with refractorythymic epithelial tumor (TET) who were enrolled in a phase II trial of pembrolizumab (NCT02607631) and 60 patients with metastatic non-small cell lung cancer (NSCLC) who received pembrolizumab or nivolumab. T-cell profiling was performed by multi-color flow cytometry using peripheral blood obtained immediately before treatment and 7 days after the first dose of anti-PD-1 antibodies. Results: Severe irAEs (≥ grade 3) occurred in 7 TET patients (22.6%) and 6 NSCLC patients (10.0%). Patients with severe irAEs exhibited a significantly lower fold increase in the frequency of effector regulatory T (eTreg) cells after anti-PD-1 treatment, higher ratio of T helper-17 (Th17) and T helper-1 cells at baseline, and higher percentage of Ki-67+cells among PD-1+CD8+T cells post-treatment. In clustering analysis, patients with severe irAEs were grouped into four distinct subtypes: Th17-related, TNF-related,Treg-related, and CD8-related. Conclusions: Severe irAEs after anti-PD-1 treatment were clustered into four immunological subtypes, indicating that development of severe irAEs is not attributed to a single mechanism. Further investigations in larger cohorts are needed to validate our current findings.

scholarly journals Determinant in Human Immunodeficiency Virus Type 1 for Efficient Replication under Cytokine-Induced CD4+ T-Helper 1 (Th1)- and Th2-Type Conditions

1999 ◽  
Vol 73 (1) ◽  
pp. 316-324 ◽  
Author(s):  
Youichi Suzuki ◽  
Yoshio Koyanagi ◽  
Yuetsu Tanaka ◽  
Tsutomu Murakami ◽  
Naoko Misawa ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Th2 Cells ◽  
T Helper ◽  
T Helper 1 ◽  
Culture Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Cytokines are potent stimuli for CD4+-T-cell differentiation. Among them, interleukin-12 (IL-12) and IL-4 induce naive CD4+ T cells to become T-helper 1 (Th1) or Th2 cells, respectively. In this study we found that macrophage-tropic human immunodeficiency virus type 1 (HIV-1) strains replicated more efficiently in IL-12-induced Th1-type cultures derived from normal CD4+ T cells than did T-cell-line-tropic (T-tropic) strains. In contrast, T-tropic strains preferentially infected IL-4-induced Th2-type cultures derived from the same donor CD4+ T cells. Additional studies using chimeric viruses demonstrated that the V3 region of HIV-1 gp120 was the principal determinant for efficiency of replication. Cell fusion analysis showed that cells expressing envelope protein from a T-tropic strain effectively fused with IL-4-induced Th2-type culture cells. Flow cytometric analysis showed that the level of CCR5 expression was higher on IL-12-induced Th1-type culture cells, whereas CXCR4 was highly expressed on IL-4-induced Th2-type culture cells, although a low level of CXCR4 expression was observed on IL-12-induced Th1-type culture cells. These results indicate that HIV-1 isolates exhibit differences in the ability to infect CD4+-T-cell subsets such as Th1 or Th2 cells and that this difference may partly correlate with the expression of particular chemokine receptors on these cells. The findings suggest that immunological conditions are one of the factors responsible for inducing selection of HIV-1 strains.

scholarly journals Thymic and Postthymic Regulation of Naïve CD4+T-Cell Lineage Fates in Humans and Mice Models

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
José E. Belizário ◽  
Wesley Brandão ◽  
Cristiano Rossato ◽  
Jean Pierre Peron
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Regulatory Cells ◽  
Transforming Growth Factor ◽  
Cell Lineage ◽  
Lymphoid Tissues ◽  
Regulatory Cells ◽  
T Helper ◽  
Mice Model ◽  
T Helper 1

Our understanding of how thymocytes differentiate into many subtypes has been increased progressively in its complexity. At early life, the thymus provides a suitable microenvironment with specific combination of stromal cells, growth factors, cytokines, and chemokines to induce the bone marrow lymphoid progenitor T-cell precursors into single-positive CD4+and CD8+T effectors and CD4+CD25+T-regulatory cells (Tregs). At postthymic compartments, the CD4+T-cells acquire distinct phenotypes which include the classical T-helper 1 (Th1), T-helper 2 (Th2), T-helper 9 (Th9), T-helper 17 (Th17), follicular helper T-cell (Tfh), and induced T-regulatory cells (iTregs), such as the regulatory type 1 cells (Tr1) and transforming growth factor-β- (TGF-β-) producing CD4+T-cells (Th3). Tregs represent only a small fraction, 5–10% in mice and 1-2% in humans, of the overall CD4+T-cells in lymphoid tissues but are essential for immunoregulatory circuits mediating the inhibition and expansion of all lineages of T-cells. In this paper, we first provide an overview of the major cell-intrinsic developmental programs that regulate T-cell lineage fates in thymus and periphery. Next, we introduce the SV40 immortomouse as a relevant mice model for implementation of new approaches to investigate thymus organogenesis, CD4 and CD8 development, and thymus cells tumorogenesis.

scholarly journals Interferon-producing Cells Fail to Induce Proliferation of Naive T Cells but Can Promote Expansion and T Helper 1 Differentiation of Antigen-experienced Unpolarized T Cells

2003 ◽  
Vol 197 (7) ◽  
pp. 899-906 ◽  
Author(s):  
Anne Krug ◽  
Ravi Veeraswamy ◽  
Andrew Pekosz ◽  
Osami Kanagawa ◽  
Emil R. Unanue ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Mhc Class Ii ◽  
Type I ◽  
T Helper ◽  
T Helper 1 ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Antigen Presenting

Interferon-producing cells (IPCs) secrete high levels of type I interferon in response to certain viruses. The lack of lineage markers, the expression of major histocompatibility complex (MHC) class II and the capacity to stimulate allogeneic T cells have led these cells to be classified as a subset of dendritic cells (DCs), called plasmacytoid DCs (PDCs). However, the role of IPCs/PDCs in initiating primary immune responses remains elusive. Here we examined the antigen presenting capacity of murine IPCs in antigen specific systems. While CD8α+ and CD11b+ DCs induced logarithmic expansion of naive CD4 and CD8 T cells, without conferring T helper commitment at a first encounter, primary IPCs lacked the ability to stimulate naive T cells. However, when antigen-experienced, nonpolarized T cells expanded by classical DC subsets, were restimulated by IPCs, they proliferated and produced high amounts of IFN-γ. These data indicate that IPCs can effectively stimulate preactivated or memory-type T cells and exert an immune-regulatory role. They also suggest that expansion of naive T cells and acquisition of effector function during antigen-specific T cell responses may involve different antigen-presenting cell (APC) types. Independent and coordinated control of T cell proliferation and differentiation would provide the immune system with greater flexibility in regulating immune responses.

scholarly journals CD4+ T Helper 1 Cells Facilitate Regression of Murine Lyme Carditis

2001 ◽  
Vol 69 (9) ◽  
pp. 5264-5269 ◽  
Author(s):  
Linda K. Bockenstedt ◽  
Insoo Kang ◽  
Christopher Chang ◽  
David Persing ◽  
Adrian Hayday ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Mrna Levels ◽  
T Helper ◽  
T Helper 1 ◽  
Lyme Carditis ◽  
Deficient Mice ◽  
Αβ T Cells ◽  
T Helper 1 Cells

ABSTRACT Murine Lyme borreliosis, caused by infection with the spirocheteBorrelia burgdorferi, results in acute arthritis and carditis that regress as a result of B. burgdorferi-specific immune responses. B. burgdorferi-specific antibodies can attenuate arthritis in mice deficient in both B cells and T cells but have no effect on carditis. Because macrophages comprise the principal immune cell in carditis, T-cell responses that augment cell-mediated immunity may be important for carditis regression. To investigate this hypothesis, we examined the course of Lyme carditis in mice selectively deficient in B cells or αβ T cells. Our results show that carditis regresses in B-cell-deficient B10.Ak mice but not in αβ T-cell-deficient mice, independently of the mouse strain background. Despite prominent macrophage infiltrates, hearts from B. burgdorferi-infected αβ T-cell-deficient mice had less mRNA for tumor necrosis factor alpha as measured by reverse transcription-PCR compared to infected control mice. Anti-inflammatory cytokine mRNA levels were equivalent. Adoptive transfer of gamma interferon-secreting CD4+ T cells into infected αβ T-cell-deficient mice promoted carditis resolution. These results show that αβ T cells can promote resolution of murine Lyme carditis and are the first demonstration of a beneficial role for CD4+ T helper 1 cells in this disease.

scholarly journals OX40L–OX40 Signaling in Atopic Dermatitis

2021 ◽  
Vol 10 (12) ◽  
pp. 2578
Author(s):  
Masutaka Furue ◽  
Mihoko Furue
Keyword(s):  
T Cells ◽  
Atopic Dermatitis ◽  
Memory T Cells ◽  
Effector Memory ◽  
T Helper ◽  
T Helper 1 ◽  
Therapeutic Success ◽  
T Helper 2 ◽  
Promising Target ◽  
Antigen Presenting

OX40 is one of the co-stimulatory molecules expressed on T cells, and it is engaged by OX40L, primarily expressed on professional antigen-presenting cells such as dendritic cells. The OX40L–OX40 axis is involved in the sustained activation and expansion of effector T and effector memory T cells, but it is not active in naïve and resting memory T cells. Ligation of OX40 by OX40L accelerates both T helper 1 (Th1) and T helper 2 (Th2) effector cell differentiation. Recent therapeutic success in clinical trials highlights the importance of the OX40L–OX40 axis as a promising target for the treatment of atopic dermatitis.

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