Cytotoxic CD4 T Cells in Antiviral Immunity

CD4 T cells that acquire cytotoxic phenotype and function have been repeatedly identified in humans, mice, and other species in response to many diverse pathogens. Since CD4 cytotoxic T cells are able to recognize antigenic determinants unique from those recognized by the parallel CD8 cytotoxic T cells, they can potentially contribute additional immune surveillance and direct effector function by lysing infected or malignant cells. Here, we briefly review much of what is known about the generation of cytotoxic CD4 T cells and describe our current understanding of their role in antiviral immunity. Furthering our understanding of the many roles of CD4 T cells during an anti-viral response is important for developing effective vaccine strategies that promote long-lasting protective immunity.

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The many faces of CD4 T cells: Roles in immunity and disease

Seminars in Immunology ◽

10.1016/j.smim.2013.11.001 ◽

2013 ◽

Vol 25 (4) ◽

pp. 249-251 ◽

Cited By ~ 6

Author(s):

Federica Sallusto ◽

Silvia Monticelli

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

The Many

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Circulating CD4 T cells elicited by endemic coronaviruses display vast disparities in abundance and functional potential linked to both antigen specificity and age

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab076 ◽

2021 ◽

Author(s):

Katherine A Richards ◽

Maryah Glover ◽

Jeremy C Crawford ◽

Paul Thomas ◽

Chantelle White ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Protective Immunity ◽

Granzyme B ◽

Antigen Specificity ◽

Functional Potential ◽

Membrane Envelope ◽

Ifn Γ ◽

Human Coronaviruses ◽

Repeated Infections

Abstract Repeated infections with endemic human coronaviruses are thought to reflect lack of long-lasting protective immunity. Here, we evaluate circulating human CD4 T cells collected prior to 2020 for reactivity towards hCoV spike proteins, probing for the ability to produce IFN-γ, IL-2 or granzyme B. We find robust reactivity to spike-derived epitopes, comparable to influenza, but highly variable abundance and functional potential across subjects, depending on age and viral antigen specificity. To explore the potential of these memory cells to be recruited in SARS-CoV-2 infection, we examined the same subjects for cross-reactive recognition of epitopes from SARS-CoV-2 nucleocapsid, membrane/envelope, and spike. The functional potential of these cross-reactive CD4 T cells was highly variable, with nucleocapsid-specific CD4 T cells, but not spike-reactive cells showing exceptionally high levels of granzyme production upon stimulation. These results are considered in light of recruitment of hCoV-reactive cells into responses of humans to SARS-CoV infections or vaccinations.

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Development of Autologous, Oligoclonal, Poorly Functioning T Lymphocytes in a Patient With Autosomal Recessive Severe Combined Immunodeficiency Caused by Defects of the Jak3 Tyrosine Kinase

Blood ◽

10.1182/blood.v91.3.949 ◽

1998 ◽

Vol 91 (3) ◽

pp. 949-955 ◽

Cited By ~ 32

Author(s):

Duilio Brugnoni ◽

Luigi D. Notarangelo ◽

Alessandra Sottini ◽

Paolo Airò ◽

Marta Pennacchio ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Tyrosine Kinase ◽

Cd4 T Cells ◽

Severe Combined Immunodeficiency ◽

Combined Immunodeficiency ◽

T Helper ◽

T Helper 1 ◽

In Vitro Susceptibility ◽

And Function

Abstract Defects of the common gamma chain subunit of the cytokine receptors (γc) or of Jak3, a tyrosine kinase required for γc signal transduction, result in T−B+ severe combined immunodeficiency (SCID). However, atypical cases, characterized by progressive development of T lymphocytes, have been also reported. We describe a child with SCID caused by Jak3 gene defects, which strongly but not completely affect Jak3 protein expression and function, who developed a substantial number (>3,000/μL) of autologous CD3+CD4+ T cells. These cells showed a primed/activated phenotype (CD45R0+ Fas+HLA-DR+ CD62Llo), defective secretion of T-helper 1 and T-helper 2 cytokines, reduced proliferation to mitogens, and a high in vitro susceptibility to spontaneous (caused by downregulation of bcl-2 expression) as well as activation-induced cell death. A restricted T-cell receptor repertoire was observed, with oligoclonal expansion within each of the dominant segments. These features resemble those observed in γc-/y and in Jak3−/−mice, in which a population of activated, anergic T cells (predominantly CD4+) also develops with age. These results suggest that residual Jak3 expression and function or other Jak3-independent signals may also permit the generation of CD4+ T cells that undergo in vivo clonal expansion in humans; however, these mechanisms do not allow development of CD8+ T cells, nor do they fully restore the functional properties of CD4+ T lymphocytes.

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CD4+T Cells Acting Independently of Antibody Contribute to Protective Immunity toPlasmodiumchabaudiInfection After Apical Membrane Antigen 1 Immunization

The Journal of Immunology ◽

10.4049/jimmunol.165.1.389 ◽

2000 ◽

Vol 165 (1) ◽

pp. 389-396 ◽

Cited By ~ 38

Author(s):

Huji Xu ◽

Anthony N. Hodder ◽

Huara Yan ◽

Pauline E. Crewther ◽

Robin F. Anders ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Protective Immunity ◽

Apical Membrane ◽

Apical Membrane Antigen 1 ◽

Apical Membrane Antigen

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Differential Expression and Function of α-Mannosidase I in Stimulated Naive and Memory CD4+ T Cells

Journal of Immunotherapy ◽

10.1097/cji.0b013e31821dcf23 ◽

2011 ◽

Vol 34 (5) ◽

pp. 428-437 ◽

Cited By ~ 8

Author(s):

Inga Gebuhr ◽

Kathrin Keeren ◽

Katrin Vogt ◽

Conny Höflich ◽

Christine Appelt ◽

...

Keyword(s):

T Cells ◽

Differential Expression ◽

Cd4 T Cells ◽

And Function ◽

Memory Cd4 T Cells

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Biology and Function of Cytotoxic T-Cells

Host Defense Dysfunction in Trauma, Shock and Sepsis ◽

10.1007/978-3-642-77405-8_32 ◽

1993 ◽

pp. 311-316

Author(s):

R. C. Bleackley

Keyword(s):

T Cells ◽

Cytotoxic T Cells ◽

And Function

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T-bet represses collagen-induced arthritis by suppressing Th17 lineage commitment through inhibition of RORγt expression and function

Scientific Reports ◽

10.1038/s41598-021-96699-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Masaru Shimizu ◽

Yuya Kondo ◽

Reona Tanimura ◽

Kotona Furuyama ◽

Masahiro Yokosawa ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

T Helper 1 ◽

Collagen Induced Arthritis ◽

Over Expression ◽

Th17 Differentiation ◽

And Function ◽

Arthritic Joints

AbstractT-bet is a key transcription factor for the T helper 1 lineage and its expression level is negatively correlated to inflammation in patients with rheumatoid arthritis (RA). Our previous study using T-bet transgenic mice revealed over-expression of T-bet completely suppressed collagen-induced arthritis (CIA), a murine model of RA, indicating a potential suppressive role of T-bet in the pathogenesis of autoimmune arthritis. Here, we show T-bet-deficiency exacerbated CIA. T-bet in CD4 + T cells, but not in CD11c + dendritic cells, was critical for regulating the production of IL-17A, IL-17F, IL-22, and TNFα from CD4 + T cells. T-bet-deficient CD4 + T cells showed higher RORγt expression and increased IL-17A production in RORγt-positive cells after CII immunization. In addition, T-bet-deficient naïve CD4 + T cells showed accelerated Th17 differentiation in vitro. CIA induced in CD4-Cre T-betfl/fl (cKO) mice was more severe and T-bet-deficient CD4 + T cells in the arthritic joints of cKO mice showed higher RORγt expression and increased IL-17A production. Transcriptome analysis of T-bet-deficient CD4 + T cells revealed that expression levels of Th17-related genes were selectively increased. Our results indicate that T-bet in CD4 + T cells repressed RORγt expression and function resulting in suppression of arthritogenic Th17 cells and CIA.

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Preclinical and clinical development of therapeutic antibodies targeting functions of CD47 in the tumor microenvironment

Antibody Therapeutics ◽

10.1093/abt/tbaa017 ◽

2020 ◽

Vol 3 (3) ◽

pp. 179-192

Author(s):

Sukhbir Kaur ◽

Kyle V Cicalese ◽

Rajdeep Banerjee ◽

David D Roberts

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Cytotoxic T Cells ◽

Regulatory Protein ◽

Immune Surveillance ◽

Hematologic Malignancies ◽

Clinical Development ◽

Surface Glycoprotein ◽

Cell Surface Glycoprotein ◽

Thrombospondin 1

ABSTRACT CD47 is a ubiquitously expressed cell surface glycoprotein that functions as a signaling receptor for thrombospondin-1 and as the counter-receptor for signal regulatory protein-α (SIRPα). Engaging SIRPα on macrophages inhibits phagocytosis, and CD47 thereby serves as a physiological marker of self. However, elevated CD47 expression on some cancer cells also protects tumors from innate immune surveillance and limits adaptive antitumor immunity via inhibitory SIRPα signaling in antigen-presenting cells. CD47 also mediates inhibitory thrombospondin-1 signaling in vascular cells, T cells, and NK cells, and blocking inhibitory CD47 signaling on cytotoxic T cells directly increases tumor cell killing. Therefore, CD47 functions as an innate and adaptive immune checkpoint. These findings have led to the development of antibodies and other therapeutic approaches to block CD47 functions in the tumor microenvironment. Preclinical studies in mice demonstrated that blocking CD47 can limit the growth of hematologic malignancies and solid tumors and enhance the efficacy of conventional chemotherapy, radiation therapy, and some targeted cancer therapies. Humanized CD47 antibodies are showing promise in early clinical trials, but side effects related to enhanced phagocytic clearance of circulating blood cells remain a concern. Approaches to circumvent these include antibody preloading strategies and development of antibodies that recognize tumor-specific epitopes of CD47, SIRPα antibodies, and bivalent antibodies that restrict CD47 blockade to specific tumor cells. Preclinical and clinical development of antibodies and related biologics that inhibit CD47/SIRPα signaling are reviewed, including strategies to combine these agents with various conventional and targeted therapeutics to improve patient outcome for various cancers.

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