IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism (original) (raw)
Related papers
IL-21 Induces Differentiation of Human Naive and Memory B Cells into Antibody-Secreting Plasma Cells
The Journal of Immunology, 2005
In this study, we report that IL-21 plays a major role in stimulating the differentiation of human B cells. When human B cells were stimulated through the BCR, IL-21 induced minimal proliferation, IgD down-modulation, and small numbers of plasma cells. In contrast, after CD40 engagement, IL-21 induced extensive proliferation, class switch recombination (CSR), and plasma cell differentiation. Upon cross-linking both BCR and CD40, IL-21 induced the largest numbers of plasma cells. IL-21 drove both postswitch memory cells as well as poorly responsive naive cord blood B cells to differentiate into plasma cells. The effect of IL-21 was more potent than the combination of IL-2 and IL-10, especially when responsiveness of cord blood B cells was examined. IL-21 costimulation potently induced the expression of both B lymphocyte-induced maturation protein-1 (BLIMP-1) and activation-induced cytidine deaminase as well as the production of large amounts of IgG from B cells. Despite the induction of activation-induced cytidine deaminase and CSR, IL-21 did not induce somatic hypermutation. Finally, IL-2 enhanced the effects of IL-21, whereas IL-4 inhibited IL-21-induced plasma cell differentiation. Taken together, our data show that IL-21 plays a central role in CSR and plasma cell differentiation during T cell-dependent B cell responses.
Distinctive characteristics of germinal center B cells
Seminars in Immunology, 1997
A cardinal property of the immune system is its ability to respond to an antigen that was encountered years before with an accelerated and enhanced secondary response. The property of anamnestic reactions depends upon the formation of long-lived compartments of specialized T and B lymphocytes called memory cells. While the origin of the memory T-cell compartment is not known, germinal centers are the specialized sites for memory B-cell generation and the immunoglobulin V-region hypermutation necessary for the affinity maturation of serum antibody. Interestingly, the peripheral differentiation pathway that leads to this most mature B-cell state begins with the recapitulation of many characters of immature B lymphocytes in bone marrow. This review describes the distinctive cellular basis of germinal center reaction and the characteristics of B cells in germinal centers that later enter the memory pool.
Canonical germinal center B cells may not dominate the memory response to antigenic challenge
Spleen and bone marrow (BM) are the major sites of antibody production and anamnestic response in systemically immunized mice. We examined the VDJ segment repertoire of antibody plaqueforming cells (APFC) in those two sites in the course of antibody responses to the hapten nitrophenyl (NP). Individual IgG APFC expressed any one of 10 V H segments of the V186.2/V3 (J558) gene family: 186.2, 102, 23, C1H4, 165.l, CH10, 3, 593.3, 24.8 and 671.5. The majority of cells in both spleen and BM expressed the V186.2 gene joined to a D segment with Tyr95. During a 2-month period after a single immunization, the V186.2 ⍣ APFC in BM accumulated 3 times as many somatic mutations than splenic APFC (average 8.5 versus 3 mutations/V H ); this process was T h dependent as shown by in vivo depletion of CD4 ⍣ lymphocytes. However, the V186.2 ⍣ APFC in both spleen and BM shared a recurrent W33L replacement, indicating their common origin from germinal centers. The APFC expressing the other (analogue) V H segments were evenly represented in the spleen and BM, but they accumulated few, if any, mutations. The anamnestic V186.2 ⍣ APFC were highly mutated both in the spleen and BM; they represented a new and unexpected clonotype. The V/D segments were joined by Gly95 instead of Tyr95, the W33L was absent and a new shared K58R replacement appeared. The APFC expressing the 'analogue' V H genes comprised 20% of the anamnestic response and did not accumulate more mutations, but their affinities were in the range of the memory V186.2 ⍣ cells. These data suggest that the late primary and secondary responses to a hapten may be born by different B cell lineages, and that some clonotypes may reach the memory pool without an extensive mutation and expansion.
CD22 is required for formation of memory B cell precursors within germinal centers
PloS one, 2017
CD22 is a BCR co-receptor that regulates B cell signaling, proliferation and survival and is required for T cell-independent Ab responses. To investigate the role of CD22 during T cell-dependent (TD) Ab responses and memory B cell formation, we analyzed Ag-specific B cell responses generated by wild-type (WT) or CD22-/- B cells following immunization with a TD Ag. CD22-/- B cells mounted normal early Ab responses yet failed to generate either memory B cells or long-lived plasma cells, whereas WT B cells formed both populations. Surprisingly, B cell expansion and germinal center (GC) differentiation were comparable between WT and CD22-/- B cells. CD22-/- B cells, however, were significantly less capable of generating a population of CXCR4hiCD38hi GC B cells, which we propose represent memory B cell precursors within GCs. These results demonstrate a novel role for CD22 during TD humoral responses evident during primary GC formation and underscore that CD22 functions not only during B ...
Journal of Experimental Medicine, 2005
Immunization with a T cell-dependent antigen elicits production of specific memory B cells and antibody-secreting cells (ASCs). The kinetic and developmental relationships between these populations and the phenotypic forms they and their precursors may take remain unclear. Therefore, we examined the early stages of a primary immune response, focusing on the appearance of antigen-specific B cells in blood. Within 1 wk, antigen-specific B cells appear in the blood with either a memory phenotype or as immunoglobulin (Ig)G1 ASCs expressing blimp-1 . The memory cells have mutated V H genes; respond to the chemokine CXCL13 but not CXCL12, suggesting recirculation to secondary lymphoid organs; uniformly express B220; show limited differentiation potential unless stimulated by antigen; and develop independently of blimp-1 expression. The antigen-specific IgG1 ASCs in blood show affinity maturation paralleling that of bone marrow ASCs, raising the possibility that this compartment is established directly by blood-borne ASCs. We find no evidence for a blimp-1 -expressing preplasma memory compartment, suggesting germinal center output is restricted to ASCs and B220 ϩ memory B cells, and this is sufficient to account for the process of affinity maturation.
IL-21 Regulates the Differentiation of a Human γδ T Cell Subset Equipped with B Cell Helper Activity
PLoS ONE, 2012
Vc9Vd2 T lymphocytes recognize nonpeptidic antigens without presentation by MHC molecules and display pleiotropic features. Here we report that coculture of Vc9Vd2 cells with phosphoantigen and IL-21 leads to selective expression of the transcription repressor Bcl-6 and polarization toward a lymphocyte subset displaying features of follicular B-helper T (T FH ) cells. T FH -like Vc9Vd2 cells have a predominant central memory (CD27 + CD45RA 2 ) phenotype and express ICOS, CD40L and CXCR5. Upon antigen activation, they secrete IL-4, IL-10 and CXCL13, and provide B-cell help for antibody production in vitro. Our findings delineate a subset of human Vc9Vd2 lymphocytes, which, upon interaction with IL-21-producing CD4 T FH cells and B cells in secondary lymphoid organs, is implicated in the production of high affinity antibodies against microbial pathogens.