Follicular T helper cells shape the HCV-specific CD4+ T cell repertoire after virus elimination

Smits, Marije J.; Zoldan, Katharina; Ishaque, Naveed; Gu, Zuguang; Jechow, Katharina; Wieland, Dominik; Conrad, Christian; Eils, Roland; Fauvelle, Catherine; Baumert, Thomas F.; Emmerich, Florian; Bengsch, Bertram; Hofmann, Maike; Thimme, Robert; Böettler, Tobias

doi:10.1172/jci129642

Cited by 42 publications

(52 citation statements)

References 56 publications

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“…Recent studies have investigated class II tetramer binding CD4 + T cells in chronic HCV infection and their fate after virus clearance. In an elegant study with samples from 44 patients tested at baseline, during and after DAA-mediated cure, Smits et al [ 47 ] showed a significant increase in HCV tetramer binding CD4 + T cells within 2 weeks of therapy initiation. This likely reflects the egress of virus-specific cells from the liver in an IP-10 gradient-dependent mechanism.…”

Section: Adaptive Immune Lymphocytes During and After Clearance Ofmentioning

confidence: 99%

“…The impact of virus clearance on these exhaustion and activation markers on CD4+ T cells is well documented. The frequency of virus-specific CD4 + T cells expressing PD-1, BTLA, and T cell Ig and ITIM domain (TGIT) stays high during and after treatment, although intensity of PD-1 expression is reduced significantly [ 47 ]. Higher levels of TIGIT expression on HCV-specific CD4 + T cells observed during CHC remains persistently elevated at least until 24 weeks from the end of DAA treatment [ 53 ].…”

Section: Adaptive Immune Lymphocytes During and After Clearance Ofmentioning

confidence: 99%

“…Higher levels of TIGIT expression on HCV-specific CD4 + T cells observed during CHC remains persistently elevated at least until 24 weeks from the end of DAA treatment [ 53 ]. There is a however normalization of activation status of antigen-specific CD4 + T cells, as indicated by the significant reduction in CD38, ICOS, and OX40 expression [ 47 ].…”

Section: Adaptive Immune Lymphocytes During and After Clearance Ofmentioning

confidence: 99%

“…Interestingly, an increase in expression of memory-associated markers CD127 and TCF-1 on antigen-specific cells occurs with viral clearance, this however is not accompanied by changes in cytokine expression patterns of these cells [ 47 ]. During CHC, a redistribution of memory CD4 + T cells at the expenses of naïve cells occurs, with memory T lymphocytes displaying an activated and exhaustive phenotype; these changes are only partially restored with virus clearance [ 54 ].…”

Section: Adaptive Immune Lymphocytes During and After Clearance Ofmentioning

confidence: 99%

“…Although circulating Tfh cells in CHC patients express and secrete less IL-21 compared to healthy subjects, they are capable of stimulating memory B cells into IgG and IgM-producing plasmablasts [ 58 , 60 ]. Smits et al demonstrated that the frequency of HCV-specific CD4 + T cells increased in circulation within two weeks of the initiation of DAA therapy [ 47 ] and the majority of these HCV-specific CD4 + T cells exhibited phenotypic and transcriptional characteristics of follicular T helper cells; these are maintained after therapy-induced elimination of persistent HCV infection. Following viral clearance with DAA, a downregulation in expression of exhaustion (PD1, BTLA, CD39, and TIGIT) and activation (CD38, ICOS, and OX40) markers and an upregulation in memory-associated markers (CD127) are detected on Tfh cells [ 47 ].…”

Section: Adaptive Immune Lymphocytes During and After Clearance Ofmentioning

confidence: 99%

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Lymphocyte Landscape after Chronic Hepatitis C Virus (HCV) Cure: The New Normal

Ghosh¹,

Romani²,

Kottilil³

et al. 2020

IJMS

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Chronic HCV (CHC) infection is the only chronic viral infection for which curative treatments have been discovered. These direct acting antiviral (DAA) agents target specific steps in the viral replication cycle with remarkable efficacy and result in sustained virologic response (SVR) or cure in high (>95%) proportions of patients. These treatments became available 6–7 years ago and it is estimated that their real impact on HCV related morbidity, including outcomes such as cirrhosis and hepatocellular carcinoma (HCC), will not be known for the next decade or so. The immune system of a chronically infected patient is severely dysregulated and questions remain regarding the immune system’s capacity in limiting liver pathology in a cured individual. Another important consequence of impaired immunity in patients cleared of HCV with DAA will be the inability to generate protective immunity against possible re-infection, necessitating retreatments or developing a prophylactic vaccine. Thus, the impact of viral clearance on restoring immune homeostasis is being investigated by many groups. Among the important questions that need to be answered are how much the immune system normalizes with cure, how long after viral clearance this recalibration occurs, what are the consequences of persisting immune defects for protection from re-infection in vulnerable populations, and does viral clearance reduce liver pathology and the risk of developing hepatocellular carcinoma in individuals cured with these agents. Here, we review the recent literature that describes the defects present in various lymphocyte populations in a CHC patient and their status after viral clearance using DAA treatments.

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Section: Adaptive Immune Lymphocytes During and After Clearance Ofmentioning

confidence: 99%

Section: Adaptive Immune Lymphocytes During and After Clearance Ofmentioning

confidence: 99%

Section: Adaptive Immune Lymphocytes During and After Clearance Ofmentioning

confidence: 99%

Section: Adaptive Immune Lymphocytes During and After Clearance Ofmentioning

confidence: 99%

Section: Adaptive Immune Lymphocytes During and After Clearance Ofmentioning

confidence: 99%

See 3 more Smart Citations

Lymphocyte Landscape after Chronic Hepatitis C Virus (HCV) Cure: The New Normal

Ghosh¹,

Romani²,

Kottilil³

et al. 2020

IJMS

View full text Add to dashboard Cite

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Antigen‐dependent multistep differentiation of T follicular helper cells and its role in SARS‐CoV‐2 infection and vaccination

Baumjohann

Fazilleau

2021

Eur J Immunol

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T follicular helper (Tfh) cells play an essential role in regulating the GC reaction and, consequently, the generation of high‐affinity antibodies and memory B cells. Therefore, Tfh cells are critical for potent humoral immune responses against various pathogens and their dysregulation has been linked to autoimmunity and cancer. Tfh cell differentiation is a multistep process, in which cognate interactions with different APC types, costimulatory and coinhibitory pathways, as well as cytokines are involved. However, it is still not fully understood how a subset of activated CD4+ T cells begins to express the Tfh cell‐defining chemokine receptor CXCR5 during the early stage of the immune response, how some CXCR5+ pre‐Tfh cells enter the B‐cell follicles and mature further into GC Tfh cells, and how Tfh cells are maintained in the memory compartment. In this review, we discuss recent advances on how antigen and cognate interactions are important for Tfh cell differentiation and long‐term persistence of Tfh cell memory, and how this is relevant to the current understanding of COVID‐19 pathogenesis and the development of potent SARS‐CoV‐2 vaccines.

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Imbalance of Regulatory and Cytotoxic SARS-CoV-2-Reactive CD4+ T Cells in COVID-19

Meckiff

Ramírez-Suástegui

Fajardo

et al. 2020

Cell

485

504

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The contribution of CD4 + T cells to protective or pathogenic immune responses to SARS-CoV-2 infection remains unknown. Here, we present single-cell transcriptomic analysis of >100,000 viral antigen-reactive CD4 + T cells from 40 COVID-19 patients. In hospitalized patients compared to non-hospitalized patients, we found increased proportions of cytotoxic follicular helper (T FH ) cells and cytotoxic T helper cells (CD4-CTLs) responding to SARS-CoV-2, and reduced proportion of SARS-CoV-2-reactive regulatory T cells (T REG ). Importantly, in hospitalized COVID-19 patients, a strong cytotoxic T FH response was observed early in the illness which correlated negatively with antibody levels to SARS-CoV-2 spike protein. Polyfunctional T helper (T H )1 and T H 17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4 + T cells compared to influenza-reactive CD4 + T cells. Together, our analyses provide insights into the gene expression patterns of SARS-CoV-2-reactive CD4 + T cells in distinct disease severities.

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Follicular T helper cells shape the HCV-specific CD4+ T cell repertoire after virus elimination

Cited by 42 publications

References 56 publications

Lymphocyte Landscape after Chronic Hepatitis C Virus (HCV) Cure: The New Normal

Lymphocyte Landscape after Chronic Hepatitis C Virus (HCV) Cure: The New Normal

Antigen‐dependent multistep differentiation of T follicular helper cells and its role in SARS‐CoV‐2 infection and vaccination

Imbalance of Regulatory and Cytotoxic SARS-CoV-2-Reactive CD4+ T Cells in COVID-19

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