ICOS enhances follicular T helper responses and deteriorates the pathogenic process of liver in mice infected with Schistosoma japonicum

AbstractBackgroundHumoral immune responses play an important role in mediating liver granulomatous inflammation and fibrosis in schistosomiasis. Follicular helper T (Tfh) cells have a central role in mediating humoral immune responses. Generation of Tfh cells depends on inducible T cell costimulator (ICOS) signaling, but the underlying molecular mechanisms are incompletely understood in pathogenesis of schistosomiasis.Methodology/Principal FindingsWe used a strain of ICOS-transgenic (Tg) mice to test the degrees of liver granulomatous inflammation and fibrosis, the frequency of splenic Tfh cells and soluble egg antigen-specific cytokine responses longitudinally in mice following Schistosoma japonicum (S. japonicum) infection. In comparison with that in wide-type (WT) mice, significantly severer liver granulomatous inflammation and fibrosis and higher mortality were observed in ICOS-Tg mice. Significantly higher frequency of splenic Tfh cells was accompanied by significantly higher levels of Bcl-6 and CXCR5 expression in the livers of ICOS-Tg mice. Furthermore, significantly higher levels of SEA-specific IL-4, IL-6, IL-10, IL-13, IL-17A, IL-21 and TGF-β1 responses, but lower levels of IFN-γ responses were detected in ICOS-Tg mice, which were abrogated by treatment with ICOS blockers in vitro. In addition, significantly higher levels of serum anti-SEA IgG were detected in ICOS-Tg mice.Conclusions/SignificanceThe ICOS-related signaling may promote the pathogenesis of murine schistosomiasis by polarizing Tfh cells, which may be immune check points for the prevention and intervention of schistosomiasis.Author summaryGranulomatous inflammation and fibrosis in the liver are the major pathogenic characteristics of schistosomiasis. ICOS is crucial for the development of Tfh cells, which are the key modulators of B cell activation and humoral immunity. However, the underlying molecular mechanisms are incompletely understood in pathogenesis of schistosomiasis. Here, our results showed that the ICOS over-expression would significantly induce severer liver inflammation and fibrosis, higher frequency of splenic Tfh, higher levels of anti-SEA IgG as well as imbalanced SEA-specific cytokine responses in ICOS-Tg mice. The findings suggested that ICOS signaling may promote the pathogenesis of murine schistosoma-related liver inflammation and fibrosis by polarizing Tfh cells. Potentially, ICOS signaling and Tfh cells may be immune check points for the prevention and intervention of schistosomiasis.

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Overexpression of Interleukin-7 Extends the Humoral Immune Response Induced by Rabies Vaccination

Journal of Virology ◽

10.1128/jvi.02324-16 ◽

2017 ◽

Vol 91 (7) ◽

Cited By ~ 11

Author(s):

Yingying Li ◽

Ming Zhou ◽

Zhaochen Luo ◽

Yachun Zhang ◽

Min Cui ◽

...

Keyword(s):

B Cells ◽

Immune Responses ◽

Neutralizing Antibodies ◽

Immunological Memory ◽

Lethal Challenge ◽

Humoral Immune ◽

Tfh Cells ◽

Humoral Immune Responses ◽

Interleukin 7 ◽

Rabies Vaccination

ABSTRACT Rabies continues to present a public health threat in most countries of the world. The most efficient way to prevent and control rabies is to implement vaccination programs for domestic animals. However, traditional inactivated vaccines used in animals are costly and have relatively low efficiency, which impedes their extensive use in developing countries. There is, therefore, an urgent need to develop single-dose and long-lasting rabies vaccines. However, little information is available regarding the mechanisms underlying immunological memory, which can broaden humoral responses following rabies vaccination. In this study, a recombinant rabies virus (RABV) that expressed murine interleukin-7 (IL-7), referred to here as rLBNSE-IL-7, was constructed, and its effectiveness was evaluated in a mouse model. rLBNSE-IL-7 induced higher rates of T follicular helper (Tfh) cells and germinal center (GC) B cells from draining lymph nodes (LNs) than the parent virus rLBNSE. Interestingly, rLBNSE-IL-7 improved the percentages of long-lived memory B cells (Bmem) in the draining LNs and plasma cells (PCs) in the bone marrow (BM) for up to 360 days postimmunization (dpi). As a result of the presence of the long-lived PCs, it also generated prolonged virus-neutralizing antibodies (VNAs), resulting in better protection against a lethal challenge than that seen with rLBNSE. Moreover, consistent with the increased numbers of Bmem and PCs after a boost with rLBNSE, rLBNSE-IL-7-immunized mice promptly produced a more potent secondary anti-RABV neutralizing antibody response than rLBNSE-immunized mice. Overall, our data suggest that overexpressing IL-7 improved the induction of long-lasting primary and secondary antibody responses post-RABV immunization. IMPORTANCE Extending humoral immune responses using adjuvants is an important method to develop long-lasting and efficient vaccines against rabies. However, little information is currently available regarding prolonged immunological memory post-RABV vaccination. In this study, a novel rabies vaccine that expressed murine IL-7 was developed. This vaccine enhanced the numbers of Tfh cells and the GC responses, resulting in upregulated quantities of Bmem and PCs. Moreover, we found that the long-lived PCs that were elicited by the IL-7-expressing recombinant virus (rLBNSE-IL-7) were able to sustain VNA levels much longer than those elicited by the parent rLBNSE virus. Upon reexposure to the pathogen, the longevous Bmem, which maintained higher numbers for up to 360 dpi with rLBNSE-IL-7 compared to rLBNSE, could differentiate into antibody-secreting cells, resulting in rapid and potent secondary production of VNAs. These results suggest that the expression of IL-7 is beneficial for induction of potent and long-lasting humoral immune responses.

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Persistent Simian Immunodeficiency Virus Infection Drives Differentiation, Aberrant Accumulation, and Latent Infection of Germinal Center Follicular T Helper Cells

Journal of Virology ◽

10.1128/jvi.02471-15 ◽

2015 ◽

Vol 90 (3) ◽

pp. 1578-1587 ◽

Cited By ~ 36

Author(s):

Huanbin Xu ◽

Xiaolei Wang ◽

Naomi Malam ◽

Pyone P. Aye ◽

Xavier Alvarez ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

T Helper Cells ◽

Latent Infection ◽

T Helper ◽

Humoral Immune ◽

Tfh Cells ◽

Humoral Immune Responses ◽

Immunodeficiency Virus ◽

Follicular T Helper Cells

ABSTRACTCD4+follicular T helper (Tfh) cells play a prominent role in humoral immune responses, but the mechanisms of their accumulation and infection in AIDS remain unclear. Here we found that germinal center (GC) Tfh cells, defined here as CXCR5+PD-1HIGHCD4+T cells, do not express the HIV coreceptor CCR5 yet serve as a latent reservoir in GCs. With disease progression, an expansion of GC Tfh cells is accompanied by increases in dysfunctional CD8+T cells. In contrast, Tfh precursor (CXCR5−CD4+T) cells in lymph nodes do express CCR5 and differentiate into GC Tfh cells following interleukin-6 (IL-6) and IL-21 stimulation, and viral DNA is detectable in fully differentiated GC Tfh cellsex vivo. This suggests that SIV-infected GC Tfh cells may be derived from Tfh precursor cell subsets that become infected in marginal zones and then migrate into GCs as fully mature GC Tfh cells that serve as persistent virus reservoirs. These findings suggest that viral persistence in lymph nodes drives compensatory differentiation, aberrant accumulation, and latent infection of GC Tfh cells, resulting in marked impairment of humoral immune responses.IMPORTANCEGeneration of antibodies that can effectively eliminate viruses requires interactions of B cells with highly specialized T cells in GCs of lymphoid tissues called follicular T helper cells. Here we show that in simian immunodeficiency virus infection, these cells are initially infected in a precursor stage that leads to alterations in their homing, accumulation, and function that may be responsible for the inability of human immunodeficiency virus-infected patients to generate effective antibody responses.

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Helminth Protein Vaccine Induced Follicular T Helper Cell for Enhancement of Humoral Immunity againstSchistosoma japonicum

BioMed Research International ◽

10.1155/2013/798164 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Jingyao Zhang ◽

Wenjuan Gao ◽

Qirui Guo ◽

Bobo Huang ◽

Bin Wang ◽

...

Keyword(s):

B Cells ◽

Immune Responses ◽

Humoral Immunity ◽

Molecular Targets ◽

T Helper Cell ◽

Protein Vaccine ◽

T Helper ◽

Humoral Immune ◽

Tfh Cells ◽

Humoral Immune Responses

Protein vaccines combined with adjuvants have been widely used to induce immune responses, especially the humoral immune response, against molecular targets including parasites. Follicular T helper (Tfh) cells are the specialized providers of B-cell help, however, the induction of Tfh cells in protein vaccination has been rarely studied. Here, we report that theSchistosoma japonicumrecombinant protein (SjGST-32) combined with tacrolimus (FK506) augmented the induction of Tfh cells, which expressed the canonical markers CXCR5, BCL6, and IL-21, and enhanced the humoral immune responses in BALB/c mice. Furthermore, the expression of IL-21R on germinal center (GC) B cells and memory B cells increased in immunized mice, which indicated that IL-21 from the induced Tfh cells interacted with IL-21R for activation of B cells and maintenance of long-lived humoral immunity. Our results suggest that helminth protein vaccine combined with FK506 induces Tfh cell for stimulating humoral immune responses and inducing long-lived humoral immunity.

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DC Subsets Regulate Humoral Immune Responses by Supporting the Differentiation of Distinct Tfh Cells

Frontiers in Immunology ◽

10.3389/fimmu.2019.01134 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 9

Author(s):

Aurélie Bouteau ◽

Jérôme Kervevan ◽

Qingtai Su ◽

Sandra M. Zurawski ◽

Vanessa Contreras ◽

...

Keyword(s):

Immune Responses ◽

Humoral Immune ◽

Tfh Cells ◽

Humoral Immune Responses

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Langerhans cells and cDC1s play redundant roles in mRNA-LNP induced protective anti-influenza and anti-SARS-CoV-2 responses

10.1101/2021.08.01.454662 ◽

2021 ◽

Author(s):

Sonia Ndeupen ◽

Aurelie Bouteau ◽

Christopher Herbst ◽

Zhen Qin ◽

Zachary Hutchins ◽

...

Keyword(s):

Immune Responses ◽

Langerhans Cells ◽

Lethal Challenge ◽

Humoral Immune ◽

Adaptive Immune ◽

Tfh Cells ◽

Humoral Immune Responses ◽

Follicular Helper ◽

Independent Mechanism ◽

Antibody Titers

Nucleoside modified mRNA combined with Acuitas Therapeutics' lipid nanoparticles (LNP) have been shown to support robust humoral immune responses in many preclinical animal vaccine studies and later in humans with the SARS-CoV-2 vaccination. We recently showed that this platform is highly inflammatory due to the LNPs' ionizable lipid component. The inflammatory property is key to support the development of potent humoral immune responses. However, the mechanism by which this platform drives T follicular helper cells (Tfh) and humoral immune responses remains unknown. Here we show that lack of Langerhans cells or cDC1s neither significantly affected the induction of PR8 HA and SARS-CoV-2 RBD-specific Tfh cells and humoral immune responses, nor susceptibility towards the lethal challenge of influenza and SARS-CoV-2. However, the combined deletion of these two DC subsets led to a significant decrease in the induction of PR8 HA and SARS-CoV-2 RBD-specific Tfh cell and humoral immune responses. Despite these observed defects, the still high antibody titers were sufficient to confer protection towards lethal viral challenges. We further found that IL-6, but not neutrophils, was required to generate Tfh cells and antibody responses. In summary, here we bring evidence that the mRNA-LNP platform can support protective adaptive immune responses in the absence of specific DC subsets through an IL-6 dependent and neutrophil independent mechanism.

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