Fidelity of Pathogen-Specific CD4+ T Cells to the Th1 Lineage Is Controlled by Exogenous Cytokines, Interferon-γ Expression, and Pathogen Lifestyle

Background: Myelin-specific T cells are implicated in multiple sclerosis (MS) and drive experimental autoimmune encephalomyelitis (EAE). EAE is commonly induced with short peptides, whereas in MS, whole myelin proteins are available for immune response. We asked whether immunization with the immunoglobulin-like domain of myelin oligodendrocyte glycoprotein (MOGIgd, residues 1–125) might induce distinct CD4+ T-cell response and/or a stronger CD8+ T-cell response, compared to the 21 amino acid immunodominant MHC II-associating peptide (p35–55). Objectives: Compare both EAE and T-cell responses in C57BL/6 mice immunized with MOGIgd and MOG p35–55. Methods: Cytokine production, and chemokine receptor expression by CD4+ and CD8+ T cells in the mouse central nervous system (CNS), were analyzed by flow cytometry. Results: MOGIgd triggered progression to more severe EAE than MOG p35–55, despite similar time of onset and overall incidence. EAE in MOGIgd-immunized mice was characterized by an increased percentage of CXCR3+ interferon-γ-producing CD4+ T cells in CNS. The CD8+ T-cell response to both immunogens was similar. Conclusions: Increased incidence of severe disease following MOGIgd immunization, accompanied by an increased percentage of CD4+ T cells in the CNS expressing CXCR3 and producing interferon-γ, identifies a pathogenic role for interferon-γ that is not seen when disease is induced with a single Major Histocompatibility Complex (MHC) II-associating epitope.

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The JAK inhibitor tofacitinib regulates synovitis through inhibition of interferon-γ and interleukin-17 production by human CD4+ T cells

Arthritis & Rheumatism ◽

10.1002/art.34329 ◽

2012 ◽

Vol 64 (6) ◽

pp. 1790-1798 ◽

Cited By ~ 122

Author(s):

Keisuke Maeshima ◽

Kunihiro Yamaoka ◽

Satoshi Kubo ◽

Kazuhisa Nakano ◽

Shigeru Iwata ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Interferon Γ ◽

Interleukin 17 ◽

Jak Inhibitor

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Berberine improved experimental chronic colitis by regulating interferon-γ- and IL-17A-producing lamina propria CD4+ T cells through AMPK activation

Scientific Reports ◽

10.1038/s41598-019-48331-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 12

Author(s):

Masahiro Takahara ◽

Akinobu Takaki ◽

Sakiko Hiraoka ◽

Takuya Adachi ◽

Yasuyuki Shimomura ◽

...

Keyword(s):

T Cells ◽

Lamina Propria ◽

Cd4 T Cells ◽

Interferon Γ ◽

Ampk Activation ◽

Chronic Colitis

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Clearance of HIV Type 1 Envelope Recombinant Sendai Virus Depends on CD4+T Cells and Interferon-γ But Not B Cells, CD8+T Cells, or Perforin

AIDS Research and Human Retroviruses ◽

10.1089/aid.2009.0266 ◽

2010 ◽

Vol 26 (7) ◽

pp. 783-793 ◽

Cited By ~ 5

Author(s):

Sherri L. Surman ◽

Scott A. Brown ◽

Bart G. Jones ◽

David L. Woodland ◽

Julia L. Hurwitz

Keyword(s):

T Cells ◽

B Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Sendai Virus ◽

Interferon Γ ◽

Hiv Type 1

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Interleukin (IL)-6 Directs the Differentiation of IL-4–producing CD4+ T Cells

Journal of Experimental Medicine ◽

10.1084/jem.185.3.461 ◽

1997 ◽

Vol 185 (3) ◽

pp. 461-470 ◽

Cited By ~ 552

Author(s):

Mercedes Rincón ◽

Juan Anguita ◽

Tetsuo Nakamura ◽

Erol Fikrig ◽

Richard A. Flavell

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Antigen Presenting Cells ◽

Interferon Γ ◽

T Helper Cell ◽

Th2 Cells ◽

T Helper ◽

Key Factor ◽

Antigen Presenting ◽

Potent Factor

Interleukin (IL)-4 is the most potent factor that causes naive CD4+ T cells to differentiate to the T helper cell (Th) 2 phenotype, while IL-12 and interferon γ trigger the differentiation of Th1 cells. However, the source of the initial polarizing IL-4 remains unclear. Here, we show that IL-6, probably secreted by antigen-presenting cells, is able to polarize naive CD4+ T cells to effector Th2 cells by inducing the initial production of IL-4 in CD4+ T cells. These results show that the nature of the cytokine (IL-12 or IL-6), which is produced by antigen-presenting cells in response to a particular pathogen, is a key factor in determining the nature of the immune response.

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Interferon-α Upregulates Both Interleukin-10 and Interferon-γ Production by Human CD4+ T Cells

Blood ◽

10.1182/blood.v89.3.1110 ◽

1997 ◽

Vol 89 (3) ◽

pp. 1110-1110 ◽

Cited By ~ 20

Author(s):

Liliane Schandené ◽

Elie Cogan ◽

Alain Crusiaux ◽

Michel Goldman

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Interleukin 10 ◽

Interferon Γ ◽

Interferon Α

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Interleukin 2 is an Upstream Regulator of CD4+ T Cells From Visceral Leishmaniasis Patients With Therapeutic Potential

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz074 ◽

2019 ◽

Vol 220 (1) ◽

pp. 163-173 ◽

Cited By ~ 5

Author(s):

Shashi Bhushan Chauhan ◽

Rebecca Faleiro ◽

Rajiv Kumar ◽

Susanna Ng ◽

Bhawana Singh ◽

...

Keyword(s):

T Cells ◽

Visceral Leishmaniasis ◽

Cd4 T Cells ◽

Leishmania Donovani ◽

Therapeutic Potential ◽

Interleukin 2 ◽

Interferon Γ ◽

Immune Functions ◽

T Regulatory Cell ◽

Upstream Regulator

Abstract Control of visceral leishmaniasis (VL) caused by Leishmania donovani requires interferon-γ production by CD4+ T cells. In VL patients, antiparasitic CD4+ T-cell responses are ineffective for unknown reasons. In this study, we measured the expression of genes associated with various immune functions in these cells from VL patients and compared them to CD4+ T cells from the same patients after drug treatment and from endemic controls. We found reduced GATA3, RORC, and FOXP3 gene expression in CD4+ T cells of VL patients, associated with reduced Th2, Th17, and FOXP3+CD4+ T regulatory cell frequencies in VL patient blood. Interleukin 2 (IL-2) was an important upstream regulator of CD4+ T cells from VL patients, and functional studies demonstrated the therapeutic potential of IL-2 for improving antiparasitic immunity. Together, these results provide new insights into the characteristics of CD4+ T cells from VL patients that can be used to improve antiparasitic immune responses.

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Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome

Blood ◽

10.1182/blood-2010-05-285080 ◽

2010 ◽

Vol 116 (19) ◽

pp. 3818-3827 ◽

Cited By ~ 114

Author(s):

Lis R. V. Antonelli ◽

Yolanda Mahnke ◽

Jessica N. Hodge ◽

Brian O. Porter ◽

Daniel L. Barber ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Immune Reconstitution Inflammatory Syndrome ◽

Cd4 T Cells ◽

Immune Reconstitution ◽

Interferon Γ ◽

Effector Memory ◽

Hiv Patients ◽

Inflammatory Syndrome

Abstract Immune reconstitution inflammatory syndrome (IRIS) is a considerable problem in the treatment of HIV-infected patients. To identify immunologic correlates of IRIS, we characterized T-cell phenotypic markers and serum cytokine levels in HIV patients with a range of different AIDS-defining illnesses, before and at regular time points after initiation of antiretroviral therapy. Patients developing IRIS episodes displayed higher frequencies of effector memory, PD-1+, HLA-DR+, and Ki67+ CD4+ T cells than patients without IRIS. Moreover, PD-1+ CD4+ T cells in IRIS patients expressed increased levels of LAG-3, CTLA-4, and ICOS and had a Th1/Th17 skewed cytokine profile upon polyclonal stimulation. Elevated PD-1 and Ki67 expression was also seen in regulatory T cells of IRIS patients. Furthermore, IRIS patients displayed higher serum interferon-γ, compared with non-IRIS patients, near the time of their IRIS events and higher serum interleukin-7 levels, suggesting that the T-cell populations are also exposed to augmented homeostatic signals. In conclusion, our findings indicate that IRIS appears to be a predominantly CD4-mediated phenomenon with reconstituting effector and regulatory T cells showing evidence of increased activation from antigenic exposure. These studies are registered online at http://clinicaltrials.gov as NCT00557570 and NCT00286767.

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