scholarly journals Cytolytic memory CD4+ T cell clonotypes are expanded during Plasmodium falciparum infection

2021 ◽  
Author(s):  
Raquel Furtado ◽  
Fabien Delahaye ◽  
Jinghang Zhang ◽  
Joowhan Sung ◽  
Paul Karell ◽  
...  
Keyword(s):  
T Cells ◽  
Plasmodium Falciparum ◽  
T Cell ◽  
Malaria Infection ◽  
Clinical Symptoms ◽  
Severe Disease ◽  
Cd4 T Cell ◽  
Effective Vaccine ◽  
T Helper 1 ◽  
Endemic Region

Plasmodium falciparum (Pf) malaria causes high rates of morbidity and mortality and lacks a sufficiently effective vaccine. Clinical immunity develops in residents of malaria endemic regions which confers reduced clinical symptoms during infection and protection against severe disease. We hypothesized that understanding the immune mechanisms of clinical immunity could inform vaccine design to improve efficacy. We compared the peripheral blood cellular and humoral immune responses during a mild episode of Pf malaria infection. Participants were classified as either clinically susceptible or clinically protected, based on the number of recurrent clinical infections over an 18-month longitudinal study in a malaria endemic region in Malawi. Susceptible participants had three or more recurrent clinical episodes while clinically immune individuals had one or none. Protected participants exhibited higher plasma immunoglobulin G (IgG) breadth and titers against Pf antigens, and greater antibody (Ab)-dependent Pf opsonization compared to susceptible participants. Using high dimensional mass cytometry (CyTOF), spectral flow cytometry and single-cell transcriptomic analyses, we identified expanded memory CD4+ T cell clones sharing identical T cell receptor clonotypes in the blood of protected participants during malaria infection. These cells express a strong cytolytic T helper 1 effector program with transcripts encoding granzymes (A, B, H, M), granulysin, NKG7 and the Zeb2 master transcriptional regulator of terminally differentiated effector T cells. Memory CD4+ T cells expressing Zeb2+ were CD39hiTIGIThi and expressed multiple chemotactic and checkpoint inhibitory receptors, although the cellular levels of several of these receptors were reduced in protected compared to susceptible individuals. We propose that clonally expanded Zeb2+ cytolytic memory CD4+ Th1 cells could represent essential contributors to clinical immunity against Pf malaria.

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 CD4+ T cell effector commitment coupled to self-renewal by asymmetric cell divisions

2016 ◽  
Vol 214 (1) ◽  
pp. 39-47 ◽  
Author(s):  
Simone A. Nish ◽  
Kyra D. Zens ◽  
Radomir Kratchmarov ◽  
Wen-Hsuan W. Lin ◽  
William C. Adams ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Fate ◽  
Clonal Selection ◽  
Cd4 T Cell ◽  
T Helper 1 ◽  
Self Renewal ◽  
Effector Cells ◽  
Follicular Helper

Upon infection, an activated CD4+ T cell produces terminally differentiated effector cells and renews itself for continued defense. In this study, we show that differentiation and self-renewal arise as opposing outcomes of sibling CD4+ T cells. After influenza challenge, antigen-specific cells underwent several divisions in draining lymph nodes (LN; DLNs) while maintaining expression of TCF1. After four or five divisions, some cells silenced, whereas some cells maintained TCF1 expression. TCF1-silenced cells were T helper 1–like effectors and concentrated in the lungs. Cells from earliest divisions were memory-like and concentrated in nondraining LN. TCF1-expressing cells from later divisions in the DLN could self-renew, clonally yielding a TCF1-silenced daughter cell as well as a sibling cell maintaining TCF1 expression. Some TCF1-expressing cells in DLNs acquired an alternative, follicular helper-like fate. Modeled differentiation experiments in vitro suggested that unequal PI3K/mechanistic target of rapamycin signaling drives intraclonal cell fate heterogeneity. Asymmetric division enables self-renewal to be coupled to production of differentiated CD4+ effector T cells during clonal selection.

scholarly journals Melanoma Cells Present a MAGE-3 Epitope to CD4+ Cytotoxic T Cells in Association with Histocompatibility Leukocyte Antigen DR11

1999 ◽  
Vol 189 (5) ◽  
pp. 871-876 ◽  
Author(s):  
Simona Manici ◽  
Tiziana Sturniolo ◽  
Maria Adele Imro ◽  
Juergen Hammer ◽  
Francesco Sinigaglia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cytotoxic T Cells ◽  
Epitope Prediction ◽  
Melanoma Cells ◽  
Cd4 T Cell ◽  
T Cell Epitopes ◽  
T Helper 1 ◽  
Leukocyte Antigen

In this study we used TEPITOPE, a new epitope prediction software, to identify sequence segments on the MAGE-3 protein with promiscuous binding to histocompatibility leukocyte antigen (HLA)-DR molecules. Synthetic peptides corresponding to the identified sequences were synthesized and used to propagate CD4+ T cells from the blood of a healthy donor. CD4+ T cells strongly recognized MAGE-3281–295 and, to a lesser extent, MAGE-3141–155 and MAGE-3146–160. Moreover, CD4+ T cells proliferated in the presence of recombinant MAGE-3 after processing and presentation by autologous antigen presenting cells, demonstrating that the MAGE-3 epitopes recognized are naturally processed. CD4+ T cells, mostly of the T helper 1 type, showed specific lytic activity against HLA-DR11/MAGE-3–positive melanoma cells. Cold target inhibition experiments demonstrated indeed that the CD4+ T cells recognized MAGE-3281–295 in association with HLA-DR11 on melanoma cells. This is the first evidence that a tumor-specific shared antigen forms CD4+ T cell epitopes. Furthermore, we validated the use of algorithms for the prediction of promiscuous CD4+ T cell epitopes, thus opening the possibility of wide application to other tumor-associated antigens. These results have direct implications for cancer immunotherapy in the design of peptide-based vaccines with tumor-specific CD4+ T cell epitopes.

scholarly journals Attenuated PfSPZ Vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection

2017 ◽  
Vol 114 (10) ◽  
pp. 2711-2716 ◽  
Author(s):  
Kirsten E. Lyke ◽  
Andrew S. Ishizuka ◽  
Andrea A. Berry ◽  
Sumana Chakravarty ◽  
Adam DeZure ◽  
...  
Keyword(s):  
T Cells ◽  
Plasmodium Falciparum ◽  
T Cell ◽  
Vaccine Strain ◽  
Malaria Infection ◽  
Malaria Vaccine ◽  
Protective Efficacy ◽  
Vaccine Dose ◽  
Human Malaria ◽  
Controlled Human Malaria Infection

A live-attenuated malaria vaccine,Plasmodium falciparumsporozoite vaccine (PfSPZ Vaccine), confers sterile protection against controlled human malaria infection (CHMI) withPlasmodium falciparum(Pf) parasites homologous to the vaccine strain up to 14 mo after final vaccination. No injectable malaria vaccine has demonstrated long-term protection against CHMI using Pf parasites heterologous to the vaccine strain. Here, we conducted an open-label trial with PfSPZ Vaccine at a dose of 9.0 × 105PfSPZ administered i.v. three times at 8-wk intervals to 15 malaria-naive adults. After CHMI with homologous Pf parasites 19 wk after final immunization, nine (64%) of 14 (95% CI, 35–87%) vaccinated volunteers remained without parasitemia compared with none of six nonvaccinated controls (P= 0.012). Of the nine nonparasitemic subjects, six underwent repeat CHMI with heterologous Pf7G8 parasites 33 wk after final immunization. Five (83%) of six (95% CI, 36–99%) remained without parasitemia compared with none of six nonvaccinated controls. PfSPZ-specific T-cell and antibody responses were detected in all vaccine recipients. Cytokine production by T cells from vaccinated subjects after in vitro stimulation with homologous (NF54) or heterologous (7G8) PfSPZ were highly correlated. Interestingly, PfSPZ-specific T-cell responses in the blood peaked after the first immunization and were not enhanced by subsequent immunizations. Collectively, these data suggest durable protection against homologous and heterologous Pf parasites can be achieved with PfSPZ Vaccine. Ongoing studies will determine whether protective efficacy can be enhanced by additional alterations in the vaccine dose and number of immunizations.

scholarly journals Profile of SARS-CoV-2-specific CD4 T cell response: Relationship with disease severity and impact of HIV-1 and active Mycobacterium tuberculosis co-infection

2021 ◽  
Author(s):  
Catherine Riou ◽  
Elsa du Bruyn ◽  
Cari Stek ◽  
Remy Daroowala ◽  
Rene T. Goliath ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Severity ◽  
Cell Response ◽  
Cd4 T Cells ◽  
Severe Disease ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Functions ◽  
Hiv 1

SUMMARYT cells are involved in control of COVID-19, but limited knowledge is available on the relationship between antigen-specific T cell response and disease severity. Here, we assessed the magnitude, function and phenotype of SARS-CoV-2-specific CD4 T cells in 95 hospitalized COVID-19 patients (38 of them being HIV-1 and/or tuberculosis (TB) co-infected) and 38 non-COVID-19 patients, using flow cytometry. We showed that SARS-CoV-2-specific CD4 T cell attributes, rather than magnitude, associates with disease severity, with severe disease being characterized by poor polyfunctional potential, reduced proliferation capacity and enhanced HLA-DR expression. Moreover, HIV-1 and TB co-infection skewed the SARS-CoV-2 T cell response. HIV-1 mediated CD4 T cell depletion associated with suboptimal T cell and humoral immune responses to SARS-CoV-2; and a decrease in the polyfunctional capacity of SARS-CoV-2-specific CD4 T cells was observed in COVID-19 patients with active TB. Our results also revealed that COVID-19 patients displayed reduced frequency of Mtb-specific CD4 T cells, with possible implications for TB disease progression. There results corroborate the important role of SARS-CoV-2-specific T cells in COVID-19 pathogenesis and support the concept of altered T cell functions in patients with severe disease.

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.

scholarly journals Role of CD4+ T Cells in the Control of Viral Infections: Recent Advances and Open Questions

2021 ◽  
Vol 22 (2) ◽  
pp. 523
Author(s):  
Jérôme Kervevan ◽  
Lisa A. Chakrabarti
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Fate ◽  
Cd4 T Cells ◽  
Viral Infections ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
T Helper 1 ◽  
Recent Advances

CD4+ T cells orchestrate adaptive immune responses through their capacity to recruit and provide help to multiple immune effectors, in addition to exerting direct effector functions. CD4+ T cells are increasingly recognized as playing an essential role in the control of chronic viral infections. In this review, we present recent advances in understanding the nature of CD4+ T cell help provided to antiviral effectors. Drawing from our studies of natural human immunodeficiency virus (HIV) control, we then focus on the role of high-affinity T cell receptor (TCR) clonotypes in mediating antiviral CD4+ T cell responses. Last, we discuss the role of TCR affinity in determining CD4+ T cell differentiation, reviewing the at times divergent studies associating TCR signal strength to the choice of a T helper 1 (Th1) or a T follicular helper (Tfh) cell fate.

scholarly journals The Many Faces of CD4+ T Cells: Immunological and Structural Characteristics

2020 ◽  
Vol 22 (1) ◽  
pp. 73
Author(s):  
Demetra S. M. Chatzileontiadou ◽  
Hannah Sloane ◽  
Andrea T. Nguyen ◽  
Stephanie Gras ◽  
Emma J. Grant
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Molecular Mechanisms ◽  
Structural Characteristics ◽  
Cd4 T Cell ◽  
T Helper 1 ◽  
Follicular Helper ◽  
Integral Role ◽  
The Many

As a major arm of the cellular immune response, CD4+ T cells are important in the control and clearance of infections. Primarily described as helpers, CD4+ T cells play an integral role in the development and activation of B cells and CD8+ T cells. CD4+ T cells are incredibly heterogeneous, and can be divided into six main lineages based on distinct profiles, namely T helper 1, 2, 17 and 22 (Th1, Th2, Th17, Th22), regulatory T cells (Treg) and T follicular helper cells (Tfh). Recent advances in structural biology have allowed for a detailed characterisation of the molecular mechanisms that drive CD4+ T cell recognition. In this review, we discuss the defining features of the main human CD4+ T cell lineages and their role in immunity, as well as their structural characteristics underlying their detection of pathogens.

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