scholarly journals T resident helper cells promote humoral responses in the lung

2021 ◽  
Vol 6 (55) ◽  
pp. eabb6808
Author(s):  
Nivedya Swarnalekha ◽  
David Schreiner ◽  
Ludivine C. Litzler ◽  
Saadia Iftikhar ◽  
Daniel Kirchmeier ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Infection ◽  
Respiratory Viruses ◽  
Challenge Infection ◽  
Effective Vaccine ◽  
Subsequent Infection ◽  
Vaccination Strategies ◽  
Helper Cells ◽  
Follicular Helper ◽  
Humoral Responses

Influenza is a deadly and costly infectious disease, even during flu seasons when an effective vaccine has been developed. To improve vaccines against respiratory viruses, a better understanding of the immune response at the site of infection is crucial. After influenza infection, clonally expanded T cells take up permanent residence in the lung, poised to rapidly respond to subsequent infection. Here, we characterized the dynamics and transcriptional regulation of lung-resident CD4+ T cells during influenza infection and identified a long-lived, Bcl6-dependent population that we have termed T resident helper (TRH) cells. TRH cells arise in the lung independently of lymph node T follicular helper cells but are dependent on B cells, with which they tightly colocalize in inducible bronchus-associated lymphoid tissue (iBALT). Deletion of Bcl6 in CD4+ T cells before heterotypic challenge infection resulted in redistribution of CD4+ T cells outside of iBALT areas and impaired local antibody production. These results highlight iBALT as a homeostatic niche for TRH cells and advocate for vaccination strategies that induce TRH cells in the lung.

scholarly journals The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Heather D Marshall ◽  
John P Ray ◽  
Brian J Laidlaw ◽  
Nianzhi Zhang ◽  
Dipika Gawande ◽  
...  
Keyword(s):  
T Cells ◽  
Transforming Growth Factor Beta ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Antibody Responses ◽  
T Follicular Helper Cells ◽  
High Affinity ◽  
Tfh Cells ◽  
Helper Cells ◽  
Follicular Helper

T follicular helper cells (Tfh) are crucial for the initiation and maintenance of germinal center (GC) reactions and high affinity, isotype-switched antibody responses. In this study, we demonstrate that direct TGF-β signaling to CD4 T cells is important for the formation of influenza-specific Tfh cells, GC reactions, and development of isotype-switched, flu-specific antibody responses. Early during infection, TGF-β signaling suppressed the expression of the high affinity IL-2 receptor α chain (CD25) on virus-specific CD4 T cells, which tempered IL-2 signaling and STAT5 and mammalian target of rapamycin (mTOR) activation in Tfh precursor CD4 T cells. Inhibition of mTOR allowed for the differentiation of Tfh cells in the absence of TGF-βR signaling, suggesting that TGF-β insulates Tfh progenitor cells from IL-2-delivered mTOR signals, thereby promoting Tfh differentiation during acute viral infection. These findings identify a new pathway critical for the generation of Tfh cells and humoral responses during respiratory viral infections.

scholarly journals Mucosal T follicular helper cells in SIV-infected rhesus macaques: contributing role of IL-27

2019 ◽  
Vol 12 (4) ◽  
pp. 1038-1054 ◽  
Author(s):  
Félicien Moukambi ◽  
Henintsoa Rabezanahary ◽  
Yasmina Fortier ◽  
Vasco Rodrigues ◽  
Julien Clain ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd4 T Cells ◽  
Rhesus Macaques ◽  
T Follicular Helper Cells ◽  
Mesenteric Lymph Nodes ◽  
Tfh Cells ◽  
Helper Cells ◽  
Follicular Helper ◽  
Memory Cd4 T Cells

AbstractMesenteric lymph nodes (MLNs), that drain the large and small intestine, are critical sites for the induction of oral tolerance. Although depletion of CD4 T cells in the intestinal lamina propria is a hallmark of HIV infection, CD4 T cell dynamics in MLNs is less known due to the lack of accessibility to these LNs. We demonstrate the early loss of memory CD4 T cells, including T follicular helper cells (Tfh) and a remodeling of MLN architecture in SIV-infected rhesus macaques (RMs). Along with the loss of Tfh cells, we observe the loss of memory B cells and of germinal center B cells. Tfh cells display a Th1 profile with increased levels of the transcription factors that negatively impact on Tfh differentiation and of Stat5 phosphorylation. MLNs of SIV-infected RMs display lower mRNA transcripts encoding for IL-12, IL-23, and IL-35, whereas those coding for IL-27 are not impaired in MLNs. In vitro, IL-27 negatively impacts on Tfh cells and recapitulates the profile observed in SIV-infected RMs. Therefore, early defects of memory CD4 T cells, as well of Tfh cells in MLNs, which play a central role in regulating the mucosal immune response, may have major implications for Aids.

scholarly journals Ibrutinib-Mediated Inhibition of cGVHD Pathogenic Pre-Germinal Center B-Cells and Follicular Helper Cells While Preserving Immune Memory and Th1 T-Cells

2018 ◽  
Vol 24 (3) ◽  
pp. S20-S21 ◽  
Author(s):  
Bita Sahaf ◽  
Dmitry Tebaykin ◽  
Melissa Hopper ◽  
Patricia Cheung ◽  
Fabiola Bittencourt ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Germinal Center ◽  
Immune Memory ◽  
Helper Cells ◽  
Follicular Helper ◽  
Germinal Center B Cells

B-108 Germinal center CD8 T cells can be redirected to eliminate HIV-expressing T follicular helper cells

2014 ◽  
Vol 67 ◽  
pp. 47
Author(s):  
Constantinos Petrovas ◽  
Sara Ferrando-Martinez ◽  
Amarendra Pegu ◽  
Kristin Boswell ◽  
Mangai Asokan ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Germinal Center ◽  
T Follicular Helper Cells ◽  
Helper Cells ◽  
Follicular Helper

scholarly journals Generation of potent cellular and humoral immunity against SARS-CoV-2 antigens via conjugation to a polymeric glyco-adjuvant

2021 ◽  
Author(s):  
Laura T. Gray ◽  
Michal M. Raczy ◽  
Priscilla S. Briquez ◽  
Tiffany M. Marchell ◽  
Aaron T. Alpar ◽  
...  
Keyword(s):  
Effective Vaccine ◽  
Protein Antigens ◽  
Vaccine Platform ◽  
Robust Immune Response ◽  
Cell Responses ◽  
Follicular Helper ◽  
Th1 Cytokine ◽  
Cellular And Humoral Immunity ◽  
Humoral Responses ◽  
Antigen Presenting

The SARS-CoV-2 virus has caused an unprecedented global crisis, and curtailing its spread requires an effective vaccine which elicits a diverse and robust immune response. We have previously shown that vaccines made of a polymeric glyco-adjuvant conjugated to an antigen were effective in triggering such a response in other disease models and hypothesized that the technology could be adapted to create an effective vaccine against SARS-CoV-2. The core of the vaccine platform is the copolymer p(Man-TLR7), composed of monomers with pendant mannose or a toll-like receptor 7 (TLR7) agonist. Thus, p(Man-TLR7) is designed to target relevant antigen-presenting cells (APCs) via mannose-binding receptors and then activate TLR7 upon endocytosis. The p(Man-TLR7) construct is amenable to conjugation to protein antigens such as the Spike protein of SARS-CoV-2, yielding Spike-p(Man-TLR7). Here, we demonstrate Spike-p(Man-TLR7) vaccination elicits robust antigen-specific cellular and humoral responses in mice. In adult and elderly wild-type mice, vaccination with Spike-p(Man-TLR7) generates high and long-lasting titers of anti-Spike IgGs, with neutralizing titers exceeding levels in convalescent human serum. Interestingly, adsorbing Spike-p(Man-TLR7) to the depot-forming adjuvant alum, amplified the broadly neutralizing humoral responses to levels matching those in mice vaccinated with formulations based off of clinically-approved adjuvants. Additionally, we observed an increase in germinal center B cells, antigen-specific antibody secreting cells, activated T follicular helper cells, and polyfunctional Th1-cytokine producing CD4+ and CD8+ T cells. We conclude that Spike-p(Man-TLR7) is an attractive, next-generation subunit vaccine candidate, capable of inducing durable and robust antibody and T cell responses.

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