Editing Memory B cell (section)

== Development and activation ==

=== T cell dependent mechanisms ===
In a [[T-cell]] dependent development pathway, naïve [[follicular B cell]]s are activated by antigen-presenting [[follicular B helper T cells]] (T<sub>FH</sub>) during the initial infection, or primary [[immune response]].<ref name=":02" /> Naïve B cells circulate through follicles in secondary lymphoid organs (i.e. [[spleen]] and [[lymph node]]s) where they can be activated by a floating foreign peptide brought in through the [[lymph]] or by antigen presented by [[Antigen-presenting cell|antigen-presenting cells]] (APCs) such as [[dendritic cell]]s (DCs).<ref name=":32">{{cite journal | vauthors = Garside P, Ingulli E, Merica RR, Johnson JG, Noelle RJ, Jenkins MK | title = Visualization of specific B and T lymphocyte interactions in the lymph node | journal = Science | volume = 281 | issue = 5373 | pages = 96–99 | date = July 1998 | pmid = 9651253 | doi = 10.1126/science.281.5373.96 | bibcode = 1998Sci...281...96G }}</ref> B cells may also be activated by binding foreign antigen in the periphery where they then move into the secondary lymphoid organs.<ref name=":02" /> A signal transduced by the binding of the peptide to the B cell causes the cells to migrate to the edge of the follicle bordering the T cell area.<ref name=":32" />

The B cells internalize the foreign peptides, break them down, and express them on [[Major histocompatibility complex|class II major histocompatibility complexes]] (MHCII), which are cell surface proteins. Within the secondary lymphoid organs, most of the B cells will enter B-cell follicles where a germinal center will form. Most B cells will eventually differentiate into [[plasma cell]]s or memory B cells within the germinal center.<ref name=":02" /><ref name=":12">{{cite journal | vauthors = Suan D, Sundling C, Brink R | title = Plasma cell and memory B cell differentiation from the germinal center | journal = Current Opinion in Immunology | volume = 45 | pages = 97–102 | date = April 2017 | pmid = 28319733 | doi = 10.1016/j.coi.2017.03.006 | series = Lymphocyte development and activation * Tumour immunology }}</ref> The [[Follicular B helper T cells|T<sub>FH</sub>s]] that express T cell receptors (TCRs) cognate to the peptide (i.e. specific for the peptide-MHCII complex) at the border of the B cell follicle and T-cell zone will bind to the MHCII ligand. The T cells will then express the [[CD154|CD40 ligand (CD40L)]] molecule and will begin to secrete [[cytokine]]s which cause the B cells to proliferate and to undergo [[Immunoglobulin class switching|class switch recombination]], a mutation in the B cell's genetic coding that changes their [[Antibody|immunoglobulin]] type.<ref name=":42">{{cite journal | vauthors = Taylor JJ, Jenkins MK, Pape KA | title = Heterogeneity in the differentiation and function of memory B cells | journal = Trends in Immunology | volume = 33 | issue = 12 | pages = 590–597 | date = December 2012 | pmid = 22920843 | pmc = 3505266 | doi = 10.1016/j.it.2012.07.005 }}</ref><ref>{{cite journal | vauthors = Phan TG, Tangye SG | title = Memory B cells: total recall | journal = Current Opinion in Immunology | volume = 45 | pages = 132–140 | date = April 2017 | pmid = 28363157 | doi = 10.1016/j.coi.2017.03.005 | series = Lymphocyte development and activation * Tumour immunology }}</ref> Class switching allows memory B cells to secrete different types of antibodies in future immune responses.<ref name=":02" /> The B cells then either differentiate into [[plasma cell]]s, germinal center B cells, or memory B cells depending on the expressed [[transcription factor]]s. The activated B cells that expressed the transcription factor [[BCL6|Bcl-6]] will enter B-cell follicles and undergo germinal center reactions.<ref name=":42" />

Once inside the germinal center, the B cells undergo proliferation, followed by mutation of the genetic coding region of their [[B-cell receptor|BCR]], a process known as [[somatic hypermutation]].<ref name=":02" /> The mutations will either increase or decrease the affinity of the surface receptor for a particular antigen, a progression called [[affinity maturation]]. After acquiring these mutations, the receptors on the surface of the B cells (B cell receptors) are tested within the germinal center for their affinity to the current antigen.<ref>{{cite journal | vauthors = Allman D, Wilmore JR, Gaudette BT | title = The continuing story of T-cell independent antibodies | journal = Immunological Reviews | volume = 288 | issue = 1 | pages = 128–135 | date = March 2019 | pmid = 30874357 | pmc = 6653682 | doi = 10.1111/imr.12754 }}</ref> B cell clones with mutations that have increased the affinity of their surface receptors receive survival signals via interactions with their cognate [[Follicular B helper T cells|T<sub>FH</sub> cells.]]<ref name=":22" /><ref name=":02" /><ref>{{cite journal | vauthors = Victora GD, Nussenzweig MC | title = Germinal centers | journal = Annual Review of Immunology | volume = 30 | issue = 1 | pages = 429–457 | date = 2012-03-26 | pmid = 22224772 | doi = 10.1146/annurev-immunol-020711-075032 | s2cid = 20168324 }}</ref> The B cells that do not have high enough affinity to receive these survival signals, as well as B cells that are potentially auto-reactive, will be selected against and die through apoptosis.<ref name=":12" /> These processes increase variability at the antigen binding sites such that every newly generated B cell has a unique receptor.<ref name=":4">{{cite journal | vauthors = Shinnakasu R, Kurosaki T | title = Regulation of memory B and plasma cell differentiation | journal = Current Opinion in Immunology | volume = 45 | pages = 126–131 | date = April 2017 | pmid = 28359033 | doi = 10.1016/j.coi.2017.03.003 | series = Lymphocyte development and activation * Tumour immunology }}</ref>

After differentiation, memory B cells relocate to the periphery of the body where they will be more likely to encounter antigen in the event of a future exposure.<ref name=":12" /><ref name=":22" /><ref name=":02" /> Many of the circulating B cells become concentrated in areas of the body that have a high likelihood of coming into contact with antigen, such as the [[Peyer's patch]].

The process of differentiation into memory B cells within the germinal center is not yet fully understood.<ref name=":02" /> Some researchers hypothesize that differentiation into memory B cells occurs randomly.<ref name=":12" /><ref name=":3"/> Other hypotheses propose that the [[transcription factor]] NF-κB and the [[cytokine]] IL-24 are involved in the process of differentiation into memory B cells.<ref name=":4" /><ref name=":02" /> An additional hypothesis states that the B cells with relatively lower affinity for antigen will become memory B cells, in contrast to B cells with relatively higher affinity that will become plasma cells.

=== T cell independent mechanisms ===
Not all B cells present in the body have undergone somatic hypermutations. IgM+ memory B cells that have not undergone class switch recombination demonstrate that memory B cells can be produced independently of the germinal centers.