Identification and characterization of circulating human transitional B cells

Abstract

IntroductionPrimary B-cell development takes place in the bone marrow, where immature B cells must generate a functional B-cell receptor (BCR) and overcome negative selection induced by reactivity with autoantigens. [1][2][3] In mice, approximately 10% of immature B cells survive these processes and emerge from the bone marrow expressing surface immunoglobulin M (IgM) and IgD. 4 These immature "transitional" B cells transit to the spleen where they mature to become responsive to BCR-mediated signaling. [5][6][7][8][9] Only a fraction of cells survive this process of secondary (peripheral) B-cell development. 10,11 Cell surface markers have been identified that enable different stages of peripheral B-cell maturation to be characterized. In mice, heat-stable antigen (HSA, CD24) was used to distinguish immature (CD24 hi ) from mature (CD24 lo ) splenic B cells. 12 Additional cell surface markers have been used to subdivide murine splenic transitional B cells into 2 distinct populations; transitional type 1 (T1; CD24 hi , CD21 lo , CD23 lo , IgM hi , IgD lo ) and transitional T2 (CD24 hi , CD21 hi , CD23 hi , IgM hi , IgD hi ). 5 An alternative classification defines 3 types of transitional B cells using reactivity to a C1q receptor related protein to identify immature B cells and CD23 and IgM to distinguish T1 (CD23 Ϫ , IgM hi ), T2 (CD23 ϩ , IgM hi ), and T3 (CD23 ϩ , IgM lo ). 7,11 Importantly, T1 B cells are found in the bone marrow, blood, and spleen, but not lymph nodes, whereas T2 B cells are restricted to the spleen. Moreover, in vivo transfer experiments demonstrate that T1 cells give rise to T2 cells and B cells with a mature phenotype. 5,8 Most studies demonstrate that T2 cells increase in size, up-regulate survival signals, proliferate, and differentiate upon BCR ligation, whereas T1 cells die. 5,9,13 Finally, B-cell activation factor member of the tumor necrosis factor (TNF) family (BAFF) plays an integral role in the survival and maturation of murine B cells, although it remains unclear if it affects T1 or T2 B cells. 14 Most of the knowledge on primary and peripheral B-cell development is derived from mice. Many aspects of development in bone marrow appear similar in humans; however, our understanding of peripheral B-cell development is remarkably limited. As a first step in a systematic approach to address this issue, we have identified and characterized the phenotype and function of human transitional B cells from peripheral blood. Human transitional T1 B cells show some similarities, but some significant differences compared with their counterparts in murine spleen. Moreover, the presence of circulating B cells that resemble T2 B cells with respect to both phenotype and function suggests that human B-cell maturation may not be restricted to the spleen. Finally, we found increased proportions of T1 B cells in patients with systemic lupus erythematosus (SLE) that reflected peripheral lymphopenia rather than abnormalities in bone marrow production or selection in these patients with autoimmune disease...

Expansion of Functionally Immature Transitional B Cells Is Associated with Human-Immunodeficient States Characterized by Impaired Humoral Immunity

“…A similar population of B cells was also detectable in healthy individuals, albeit at a ϳ5-fold lower frequency than XLP, as well as in normal BM and cord blood (CB). The phenotype of this population resembled that of cells recently proposed to be human transitional B cells (16,17). In the current study, transitional B cells were found to display functional characteristics of immature B cells, such as the lack of expression of Bcl-2 and reduced survival, proliferation, differentiation, and chemotaxis compared with mature B cells; they also expressed unmutated Ig V region genes.…”

“…Thus, immature B cells are CD19 ϩ CD27 Ϫ CD10 ϩ IgM ϩ IgD Ϫ , while naive B cells are CD19 ϩ CD27 Ϫ IgM low IgD high , and memory B cells are CD19 ϩ CD27 ϩ and express IgM, IgG, or IgA (2,(12)(13)(14)(15). Human transitional B cells, however, remain poorly characterized, although their existence is suggested by the recent demonstration of a population of cells in peripheral blood (PB) distinguishable from mature B cells on the basis of a CD24 high CD38 high phenotype (16,17).…”

B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele

“…It could be related to the observed overall trends of reduction of CD5 þ B cells in carriers, as all transitional B cells are CD5 positive. 18,19 The development of CD5 þ B1 B cells was severely decreased in the peritoneum of CD19-deficient mice. 20,21 Whereas human CD5 þ B cells in the blood might not be the functional equivalence of mouse B1 B cells, they were equally affected in CD19-deficient mice and patients with CD19 homozygous mutations.…”

Loss of Discrete Memory B Cell Subsets Is Associated with Impaired Immunization Responses in HIV-1 Infection and May Be a Risk Factor for Invasive Pneumococcal Disease

“…Unlike switched memory B cells, IgM memory B cells do not promote long-term protective humoral immune responses and it has been proposed that this B cell subset be regarded as natural effector B cells which bridge innate and adaptive immune responses (15). The ontogeny of IgM memory B cells in humans remains unclear; one suggestion is that this B cell subset may be derived from transitional B cells which are a naive B cell population that need the spleen to complete their development to mature B cells (19,20). Increased numbers of transitional B cells are a characteristic feature of several inherited humoral immunodeficiency conditions and HIV infection (21,22) and are associated with decreased memory B cells (21).…”