Abstract:Summary
The germinal center is a dynamic microenvironment wherein B cells expressing high affinity antibody variants produced by somatic hypermutation are selected for clonal expansion by limiting numbers of T follicular helper cells
1
,
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. Although much is known about the mechanisms that control B cell selection in the germinal center, far less is understood about the clonal behavior of the T follicular helper cells that regulate this process. … Show more
“…Naive B cells and Tfh cells interact using a variety of signals, including MHC-II:TCR, CD40/CD40L, ICOS/ICOSL, SAP/SLAM and various cytokine signals which activate the B cell ( Figure 2B ). 73 , 86 Figure 2 Simplified pathway of MBC differentiation. ( A ) Naive B cells capture antigen from subcapsular macrophages, which initiates differentiation.…”
Section: Generation Of Allergen-specific Memory B Cellsmentioning
confidence: 99%
“…[69][70][71][72] Tfh cell maturation evolves via interactions with antigen-primed B cells at the T-B border. 72,73 Here, ICOS/ICOSL and CD40/CD40L costimulation and Tfhderived IL-21 retain the Tfh phenotype and allow these cells to penetrate the B-cell follicle to join or initiate GCs. 52,71 It is within the GC that the newly identified Tfh13 population has been reported, but it is unknown at what point these cells https://doi.org/10.2147/ITT.S284823…”
Section: Generation Of Allergen-specific Memory T Cellsmentioning
confidence: 99%
“…Naive B cells and Tfh cells interact using a variety of signals, including MHC-II:TCR, CD40/ CD40L, ICOS/ICOSL, SAP/SLAM and various cytokine signals which activate the B cell (Figure 2B). 73,86 Newly activated B cells adopt a transient CD38 + GL7 + phenotype that predates GC B cells or extrafollicular MBC differentiation (Figure 2C). 87 Recent evidence suggests that CSR is initiated during early interactions at the T/B cell border, possibly during this intermediate stage, rather than in the GC as classically believed.…”
Section: Generation Of Allergen-specific Memory B Cellsmentioning
confidence: 99%
“…107 Also, in secondary responses, expansion of antigen-specific B cells and class-switched antibody responses are compromised in the absence of ICOS signaling. 73,108 The fact that ICOS is essential for the maintenance of the memory Tfh cell phenotype 108 may explain the impaired secondary responses observed with ICOSL blockade. 75 Regarding OX40, OX40L-expressing DCs promote Th2 polarization, although OX40L blockade in secondary responses does not appear to skew the Th2 phenotype.…”
Section: Memory Reconstitution Of Allergymentioning
Recent evidence has highlighted the critical role of memory cells in maintaining lifelong food allergies, thereby identifying these cells as therapeutic targets. IgG
+
memory B cells replenish pools of IgE-secreting cells upon allergen exposure, which contract thereafter due to the short lifespan of tightly regulated IgE-expressing cells. Advances in the detection and highly dimensional analysis of allergen-specific B and T cells from allergic patients have provided insight on their phenotype and function. The newly identified Th2A and Tfh13 populations represent a leap in our understanding of allergen-specific T cell phenotypes, although how these populations contribute to IgE memory responses remains poorly understood. Within, we discuss the mechanisms by which memory B and T cells are activated, integrating knowledge from human systems and fundamental research. We then focus on memory reactivation, specifically, on the pathways of secondary IgE responses. Throughout, we identify areas of future research which will help identify immunotargets for a transformative therapy for food allergy.
“…Naive B cells and Tfh cells interact using a variety of signals, including MHC-II:TCR, CD40/CD40L, ICOS/ICOSL, SAP/SLAM and various cytokine signals which activate the B cell ( Figure 2B ). 73 , 86 Figure 2 Simplified pathway of MBC differentiation. ( A ) Naive B cells capture antigen from subcapsular macrophages, which initiates differentiation.…”
Section: Generation Of Allergen-specific Memory B Cellsmentioning
confidence: 99%
“…[69][70][71][72] Tfh cell maturation evolves via interactions with antigen-primed B cells at the T-B border. 72,73 Here, ICOS/ICOSL and CD40/CD40L costimulation and Tfhderived IL-21 retain the Tfh phenotype and allow these cells to penetrate the B-cell follicle to join or initiate GCs. 52,71 It is within the GC that the newly identified Tfh13 population has been reported, but it is unknown at what point these cells https://doi.org/10.2147/ITT.S284823…”
Section: Generation Of Allergen-specific Memory T Cellsmentioning
confidence: 99%
“…Naive B cells and Tfh cells interact using a variety of signals, including MHC-II:TCR, CD40/ CD40L, ICOS/ICOSL, SAP/SLAM and various cytokine signals which activate the B cell (Figure 2B). 73,86 Newly activated B cells adopt a transient CD38 + GL7 + phenotype that predates GC B cells or extrafollicular MBC differentiation (Figure 2C). 87 Recent evidence suggests that CSR is initiated during early interactions at the T/B cell border, possibly during this intermediate stage, rather than in the GC as classically believed.…”
Section: Generation Of Allergen-specific Memory B Cellsmentioning
confidence: 99%
“…107 Also, in secondary responses, expansion of antigen-specific B cells and class-switched antibody responses are compromised in the absence of ICOS signaling. 73,108 The fact that ICOS is essential for the maintenance of the memory Tfh cell phenotype 108 may explain the impaired secondary responses observed with ICOSL blockade. 75 Regarding OX40, OX40L-expressing DCs promote Th2 polarization, although OX40L blockade in secondary responses does not appear to skew the Th2 phenotype.…”
Section: Memory Reconstitution Of Allergymentioning
Recent evidence has highlighted the critical role of memory cells in maintaining lifelong food allergies, thereby identifying these cells as therapeutic targets. IgG
+
memory B cells replenish pools of IgE-secreting cells upon allergen exposure, which contract thereafter due to the short lifespan of tightly regulated IgE-expressing cells. Advances in the detection and highly dimensional analysis of allergen-specific B and T cells from allergic patients have provided insight on their phenotype and function. The newly identified Th2A and Tfh13 populations represent a leap in our understanding of allergen-specific T cell phenotypes, although how these populations contribute to IgE memory responses remains poorly understood. Within, we discuss the mechanisms by which memory B and T cells are activated, integrating knowledge from human systems and fundamental research. We then focus on memory reactivation, specifically, on the pathways of secondary IgE responses. Throughout, we identify areas of future research which will help identify immunotargets for a transformative therapy for food allergy.
“…Hence, the repertoire and specificity of Tfh cells might be critical in determining the GC longevity. Recent findings suggested that the Tfh cells undergo selection similar to GC B cells ( 106 ). In this process, Tfh cells with high affinities towards the pMHC presented by B cells are selected ( 106 ).…”
Section: Progressive Changes In T Follicular Helper Cellsmentioning
Germinal Centres (GCs) are transient structures in secondary lymphoid organs, where affinity maturation of B cells takes place following an infection. While GCs are responsible for protective antibody responses, dysregulated GC reactions are associated with autoimmune disease and B cell lymphoma. Typically, ‘normal’ GCs persist for a limited period of time and eventually undergo shutdown. In this review, we focus on an important but unanswered question – what causes the natural termination of the GC reaction? In murine experiments, lack of antigen, absence or constitutive T cell help leads to premature termination of the GC reaction. Consequently, our present understanding is limited to the idea that GCs are terminated due to a decrease in antigen access or changes in the nature of T cell help. However, there is no direct evidence on which biological signals are primarily responsible for natural termination of GCs and a mechanistic understanding is clearly lacking. We discuss the present understanding of the GC shutdown, from factors impacting GC dynamics to changes in cellular interactions/dynamics during the GC lifetime. We also address potential missing links and remaining questions in GC biology, to facilitate further studies to promote a better understanding of GC shutdown in infection and immune dysregulation.
Protein antigens are often combined with aluminum hydroxide (alum), the most commonly used adjuvant in licensed vaccines; yet the immunogenicity of alum‐adjuvanted vaccines leaves much room for improvement. Here, the authors demonstrate a strategy for codelivering an immunostimulatory cytokine, the interleukin IL‐21, with an engineered outer domain (eOD) human immunodeficiency virus gp120 Env immunogen eOD, bound together to alum to bolster the humoral immune response. In this approach, the immunogen and cytokine are co‐anchored to alum particles via a short phosphoserine (pSer) peptide linker, promoting stable binding to alum and sustained bioavailability following injection. pSer‐modified eOD and IL‐21 promote enhanced lymphatic drainage and lead to accumulation of the vaccine in B cell follicles in the draining lymph nodes. This in turn promotes enhanced T follicular helper cell priming and robust germinal center responses as well as increased antigen‐specific serum IgG titers. This is a general strategy for codelivery of immunostimulatory cytokine with immunogens providing a facile approach to modulate T cell priming and GC reactions toward enhanced protective immunity using the most common clinical vaccine adjuvant.
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