Repertoire expression in B cell subpopulations

The secondary B cell repertoire can be divided into three broad categories. The first category contains those secondary responses whose predominant clonotype or clonotype families are the same as those found in the primary response (i.e. total overlap in V gene usage), although the secondary antibodies have accumulated somatic mutations. Examples of these responses include the T15 clonotype, the \-bearing antibodies to al,3-Dex and to some extent the \NPb clonotype. In the last example, the secondary response to NP in Ighh mice is ultimately dominated by other clonotype families. The second category includes those responses whose specificities constitute a minority of the primary response but dominate the secondary response. Examples include the response to PR8-HA and the CRI in response to ARS in strain A mice. This phenotype can be explained by the preferential selection by antigen of those somatic mutants which could increase affinity. Finally, responses to 2-phenyl-5-oxazalone (phOX) by BALB/c mice, NP by C57BL/6, horse cyt c and Salmonella typhimurium by BALB/c are examples which display almost total disparities between primary and secondary responses. One possible explanation is that secondary B cells and their progenitors express variable region gene combinations that are not used by primary B cells and their precursors.

The secondary B cell repertoire, unlike the primary B cell repertoire, appears to be highly dependent upon environmental influences for its generation and regulation. Since antigenic stimulation and continued antigen selection is necessary for the establishment of secondary B cells, the secondary repertoire of individual mice within a strain can vary considerably, as seen with responses to PR8-HA and tobacco mosaic virus protein. Although still controversial, Linton and Klinman have shown the splenic progenitors to memory B cells to be separable from the precursors to primary AFCs. These secondary B cell progenitors are stimulated by lower affinity interactions than those that are required for stimulation of precursors to primary AFCs. Moreover, as shown by Linton and Klinman in vitro, and later by Nossal and Goodnow in vivo, the progenitors to memory B cells pass through a tolerance susceptible phase. In toto, secondary B cell specificity appears to be derived from a broad spectrum of potentially responsive cells which are stimulated in a much less specific fashion. These specificities can somatically mutate and continue to be selected upon positively by antigen or negatively through tolerance induction of antiself reactivities.

Another small subpopulation of murine B cells has been defined by their expression of the cell surface marker Ly-1 (CD5 in humans). Because the names applied to this subset are misleading (since CD5 clearly can be induced on 'conventional' B cells and there is a subset of cells in mice that shares many features with Ly-1 B cells (i.e. 'sister' population)), these cells are now referred to as B1 cells. The B1 cells show a variety of novel features: a novel anatomical localization (enrichment in the peritoneal cavity); early appearance in ontogeny; secretion of particular autoreactive antibodies (notably antibody to a cryptic determinant on mouse red blood cells revealed by proteolytic treatment with the enzyme bromelain (BrMRBC)); extensive capacity for self-renewal; increased frequency in autoimmune mouse strains; repetitive usage of particular germline immunoglobulin variable genes; and an apparent predisposition for unregulated growth.

Since B1 cells represent a sizable portion of neonatal splenic B cells, and fetal/neonatal-derived B cells have been shown to lack non-templated nucleo tide (N) region additions found at the VDJ junctions, it was thought that all B1 cells lacked N additions. This restriction in repertoire size has been attributed to terminal deoxynucleotidyl transferase, TdT, the enzyme which adds N nucleotides and becomes active during the first week after birth. A comparison of heavy chain sequences from B1 cells isolated at different stages of development revealed some N additions in the B1 cells of the adult population. The increased N-region diversity is found in the 'sister' population of B1 cells.

Since B1 cells develop early in ontogeny, repertoire differences may, at least in part, reflect selection by different endogenous antigens. For instance, the enrichment of B1 cells with N additions in adults may be the consequence of a selective advantage. In addition, analysis of cells responding to BrMRBC] has shown that the antigen receptor is encoded by novel VH genes (VH11 and VH12), and the significant increased frequency of VH11 usage in B1 cells is largely restricted to VHH-JH1 rearrangements. There appears to be no general overuse of particular V genes, rather such genes are used in distinctive VH-VL combinations to encode selected autoreactive antibodies. Moreover, B1 cells show a preference for using JH1 gene segments which is not observed in the conventional B cell population, and while most murine pre-B and B cells preferentially use the DSP and DFL DH gene segments in a given reading frame (RF1), cells in the 'sister' population frequently express DH genes in another reading frame (RF2).

See also: Affinity maturation; Antibodies, specificity; B lymphocyte differentiation; CD5; Clonal selection; Diversity, generation of; Hybridomas, B cell; Idiotype network; Immunoglobulin genes; Maturation of immune responses; Memory, immunological; Neonatal immune response; Polyclonal activators; Somatic mutation; Tolerance, peripheral.

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