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In addition to Bach2-requirement, optimal memory B cell generation also needs Tfh-derived IL-9 63 , and signaling through IL-9R on memory B cells is required for their recall response However, further studies are needed to fully elucidate whether this phenotype really corresponds to a committed memory B cell precursor. When these are not sufficient for immediate pathogen neutralization and elimination, memory B cells are recalled. It is therefore of vital functional importance that memory B cells are stationed at strategic sites where they can maximize their chance of encountering antigen Figure 2b.

The spleen, including the marginal zone, is a major reservoir for memory B cells in both mice and humans 14 , 65 — 67 , as is the subcapsular sinus SCS of lymph nodes This was also seen in human lymph nodes. Interestingly, the largest output from the SCS proliferative foci is short-lived plasma cells ASCs , whereas the new GC is a site for further affinity maturation and CSR with very stringent quality controls that limit plasma cell differentiation Importantly, both the SCS proliferative foci and the GC also foster memory B cells that may participate in another re-call response or be recruited later in the same response.

In addition to the spleen and lymph nodes, memory B cells are found in the bone marrow, Peyers' patches, gingiva, mucosal epithelium of tonsils, the lamina propria of the gastro-intestinal tract, and in the circulation 67 , 71 — It has not been convincingly demonstrated that the bone marrow, or any other tissue apart from the spleen and the lymph nodes contains functional memory B cells or if these memory B cells simply recirculate from the blood to the tissues.

These are all anatomical sites where antigen may breach the barriers or be carried to via the circulation, and the memory B cells located here act as sentinels should pre-existing antibodies not provide adequate protection. Figure 2. The memory recall response to secondary antigen exposure. If this is not sufficient for immediate neutralization and elimination of the antigen, memory B cells will be engaged.

This can happen either directly in the affected tissue tissue-resident memory and circulating memory B cells , or when antigen is carried to secondary lymphoid organs b. Although it is unclear which memory subset constitute the SPF, it is known that the main output is plasmablasts, but that this is also the fostering site for new memory B cells as well as cells entering GCs.

Finally, switched, high-affinity memory B cells that are double positive for CD80 and PD-L2 exclusively form new plasmablasts f. Importantly, memory B cells can also seed sites of infection, where they are maintained as tissue-resident memory B cells 77 — Here they are quickly activated after pathogen invasion without the need for antigen transportation to draining lymph nodes, thus shortening the time for plasma cell differentiation and antibody production on secondary exposure.

Interestingly, in the case of influenza virus infection, broadly reactive memory B cells are enriched in the lung-resident pool, thus conferring quick and cross-reactive protection at the site of infection Upon re-exposure to antigen, memory B cells can quickly proliferate and differentiate into plasma cells.

These surface markers denote functionally different memory B cells independent of immunoglobulin isotype 2 , 4 , 7 , 8 , Importantly, the heterogeneity of the memory B cell compartment allows for a functional breadth of memory recall responses.

Unswitched i. This breadth is particularly important for mounting rapid recall responses to variant antigens, such as influenza virus. This is comparable to the fate chosen by switched B cells in the primary GC response 54 — However, these observations may not be exclusively dependent on immunoglobulin isotype.

In humans, most studies consider plasmablasts as blood short-lived ASCs generated in acute B cell responses to infection or vaccination that transiently contribute to the serum antibody. In a secondary systemic immune response to a protein antigen such as tetanus toxoid or an inactivated influenza virus vaccine, antigen-specific IgG-secreting plasmablasts with somatically mutated VH gene rearrangements are generated from memory B cells 20 , It is also the case following influenza, Ebola, or Dengue virus infection 22 , 83 — It remains an open debate whether human plasmablasts are precursors of and how many do become LLPCs.

Evidence suggests that once the infection is cleared, the majority of ASCs undergo apoptosis, while a small proportion may go on to further differentiate into LLPCs The heterogeneity seen in human ASCs from tonsil, blood, and bone marrow reveals stages of increasing maturity, and local profiles of adhesion molecule expression suggest a multi-step model for plasma cell differentiation 82 , In human blood when plasmablasts appear between days 6 and 8 after vaccination, they are migratory and attracted by CXCL12 and could migrate to tissues, such as the bone marrow 88 , The chemokine CCL28 has also been shown to attract human bone marrow plasma cells in vitro Two interesting populations have been observed in the blood of tetanus toxoid immunized individuals: a population of migratory plasmablasts expressing CXCR3 and CXCR4, and a population resembling mature plasma cells of the bone marrow.

These findings suggest that these cells are likely to be resident LLPCs mobilized from their survival niches in the bone marrow, in competition with newly generated plasmablasts CXCL12 promotes entry of cells to the bone marrow as well as plasma cell survival An interesting study demonstrated that extracellular vesicles from bone marrow-derived MSCs support ex vivo survival of human ASCs Compared to the bone marrow niche, fibroblasts from the lymph nodes and the spleen have been poorly characterized in both mice and humans.

A few studies have shown that stromal cells in the spleen and lymph nodes might promote plasma cell survival in vitro , Recently, a new subset of fibroblasts FRCs for fibroblastic reticular cells in the lymph nodes have been described both in mice and humans as the main cell type in contact with plasma cells to guide them in their migration Plasma cells are very abundant in mucosal tissues.

They are located both in the connective tissue lamina propria and in lymphoid organs such as the tonsils in the oral cavity and Peyer's patches in the gut.

B cells in the respiratory tract and IgA responses in the gastrointestinal tract in have been nicely reviewed in Kato et al. A great variety of B cell subsets have been identified in the tonsil, spleen, and peripheral blood and represent different stages of development of a naive B cell into a memory B cell.

In the human tonsil, at least five distinct subpopulations of mature human B cells Bm1—Bm5 have been identified. Concisely, naive B cells belong to the Bm1 and Bm2 subpopulations whereas fully differentiated memory B cells belong to the Bm5 subset — Interestingly IgG transcripts in the tonsil had accumulated twice as many mutations as the IgM transcripts suggesting that reentry of selected B cells in the GC to generate higher affinity BCRs is a possibility As we previously stated, memory B cells are mainly generated in the GCs in secondary lymphoid organs.

After leaving the GCs, memory B cells either join the recirculating pool of lymphocytes, or home to antigen draining sites. Memory B cell niches outside of the blood have been described and memory B cells have been found in the bone marrow, the tonsil and the spleen An in-depth flow cytometry analysis of human bone marrow and blood samples showed that compared to the blood, the bone marrow was enriched in both MZ and switched B-cells In the spleen, two main phenotypically distinct B cell populations exist and localize to separate areas of the lymphoid tissue.

It has been demonstrated that CD, as well as CD27, are markers for memory B cells present in the human spleen The spleen is an important organ in the defense against encapsulated bacteria. These memory B cells have a mutated BCR, provide a pre-diversified immune repertoire and are involved in T-independent responses They can develop in the absence of a spleen, but splenectomy in older individuals dramatically reduces the number of blood MZ B cells , Bone marrow and blood memory B cells express surface IgG and IgA at similar frequencies, while the tonsil contained more IgA memory B cells compared to other locations.

Interestingly, the absence of spleen and tonsils does not affect secondary responses to tetanus, suggesting an organ independent maintenance and reactivation for human memory B cells Memory B cells that reside in lymphoid organs and recirculate after re-exposure to antigen are phenotypically the same and do not represent different stages of maturity. Additionally, it has been demonstrated that the human spleen is a major reservoir of long-lived vaccinia-specific memory B cells The route by which an antigen enters the body systemic vs.

Protein antigens usually trigger B cells receiving T-cell help while polysaccharide antigens induce CSR in the absence of T-cell help. Polysaccharide B cell responses to vaccination in humans have been reviewed in Mitchell et al. Antibody responses to soluble protein antigens and membrane proteins primarily induce IgG1, but are accompanied with lower levels of the other subclasses. On the other hand, antibody responses to bacterial capsular polysaccharide antigens is almost only restricted to IgG2 IgG4 antibodies are often formed following repeated or long-term exposure to antigen in a non-infectious setting Homeostatic IgA responses employ a polyreactive repertoire to bind to a broad subset of microbiota species and tend to be of low affinity.

In contrast, mucosal pathogens and vaccines elicit high-affinity, T-cell dependent antibody responses , Mucosal IgA responses through a T-cell dependent reaction that place in mucosal lymphoid follicles, such as intestinal Peyers' patches and mesenteric lymph nodes together called MALT for Mucosa-Associated Lymphoid Tissues Human IgA subtypes show distinct anatomical expression patterns, with monomeric IgA1 dominating in the serum and dimeric IgA2 in the gut Very few studies in humans have compared the induction of IgA and IgG secreting cells following various routes of immunization.

An early study compared oral, intranasal and systemic influenza virus vaccines in healthy adults. Additionally, oral and intranasal administration of antigen-induced IgA influenza-specific antibodies in external secretions In addition, immunization of African green monkeys with a live-attenuated H5N1 influenza vaccine resulted in more serum IgG neutralizing antibodies than IgA However, serum IgA antibodies had a molecular composition IgA1 vs.

IgA2 and J chain level distinct from that of IgA antibodies secreted in the gut, suggesting the involvement of different plasma cell populations Finally, analysis of long-term transcriptional profile between blood IgG and IgA influenza-reactive plasmablasts as well as influenza-negative IgA plasmablasts did not reveal any specialization based on isotype. These data suggest that IgG and IgA vaccine—positive plasmablasts are largely similar, whereas IgA vaccine—negative plasmablasts appear to be transcriptionally distinct from antigen-induced peripheral blood plasmablasts Significant efforts in the HIV field are focusing on the design of vaccines that would induce the generation of broadly neutralizing antibodies bNAbs.

Understanding the immunology behind the development of antibody potency and breadth following immunization is crucial in this context, not only to the HIV community The success of most vaccines relies on the generation of antibodies to provide protection against subsequent infection. As discussed earlier in this review, Tfh cells are critical for the production of high-affinity B cell clones in the GC and thus the generation of long term memory, i.

The feasibility of assessing GCs and Tfh responses from human lymph nodes has been limited, as GC B cells do not circulate in the blood, and lymph nodes are rarely sampled Recently, fine needle aspirates of the draining lymph nodes were used to longitudinally sample GC B cells and GC Tfh cells in non-human primates.

The lymph node fine needle aspiration technique has proven effective in terms of how many cells were recovered from the biopsy as well as in not disrupting the ongoing GC. The authors found that neutralizing antibodies in non-human primates correlate with GC B cell magnitude and Tfh help quality They also found that GCs peak weeks after the initial immunization. Proteins that are not of extreme stability can be degraded, exposing epitopes that would normally be hidden or non-existent on a more native protein conformation.

Slow immunogen release could improve the availability of intact antigen and epitopes of interest for the duration of the GC response Germline-targeting strategies aim to activate B cell precursors with potential interest for bNAbs generation, so that they will enter the GC, be selected and affinity matured and will generate memory B cells. A vaccination protocol based on B-cell lineage differs from classic protocols in the fact that they may prime with one immunogen and boost with another or with a sequence of several different immunogens — It has been recently demonstrated that only immunogens above a certain affinity and in multimeric form are capable of inducing GCs dominated by B cells from a bNAb precursor starting with low precursor frequency After the immediate threat has been dealt with, a small number of memory B cells and T cells remain on guard, ready to fight the same invader again.

Vaccines mainly work by stimulating the production of antibodies, but they can promote T-cell activity too. Checkpoint inhibitors, a type of immunotherapy, unleash T cells to fight cancer. You have been inactive for 60 minutes and will be logged out in. Any updates not saved will be lost. Home Basics. Different types of white blood cells provide protection against infections and cancer.

Call us anytime. This page was updated on November 10, B-cells vs. T-cells: What's the difference? How does the immune system work? What are B-cells? B-cells are the type of cells that produce antibodies to fight bacteria and viruses.

These antibodies are Y-shaped proteins that are specific to each pathogen and are able to lock onto the surface of an invading cell and mark it for destruction by other immune cells. B-lymphocytes and cancer have what may be described as a love-hate relationship. For example, B-cells sometimes inhibit tumor development by producing antibodies that may attack cancer cells or oncogenic viruses , such as human papillomavirus HPV , which is responsible for most cervical , anal , penile and other reproductive cancers.

Other times, regulatory B-cells may release immune-suppressive cytokines that stifle an anti-tumor response. Also, B-cells are far more likely than T-cells to mutate into a liquid cancer such as chronic lymphocytic leukemia CLL or B-cell lymphoma. Liu, L. Nature , — Grifoni, A. Cell , — Juno, J. Article PubMed Google Scholar. Tang, F. Lack of peripheral memory B cell responses in recovered patients with severe acute respiratory syndrome: a six-year follow-up study. Le Bert, N. Download references.

You can also search for this author in PubMed Google Scholar. Correspondence to Rebecca J. Reprints and Permissions. Cox, R. Nat Rev Immunol 20, — Download citation. Published : 24 August Issue Date : October Anyone you share the following link with will be able to read this content:.

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