Human B-1 cells take the stage

Abstract

B-1 cells play critical roles in defending against microbial invasion and in housekeeping removal of cellular debris. B-1 cells secrete natural antibody and manifest functions that influence T cell expansion and differentiation and in these and other ways differ from conventional B-2 cells. B-1 cells were originally studied in mice where they are easily distinguished from B-2 cells, but their identity in the human system remained poorly defined for many years. Recently, functional criteria for human B-1 cells were established on the basis of murine findings, and reverse engineering resulted in identification of the phenotypic profile, CD20(+)CD27(+)CD43(+)CD70(-), for B-1 cells found in both umbilical cord blood and adult peripheral blood. Human B-1 cells may contribute to multiple disease states through production of autoantibody and stimulation/modulation of T cell activity. Human B-1 cells could be a rich source of antibodies useful in treating diseases present in elderly populations where natural antibody protection may have eroded. Manipulation of human B-1 cell numbers and/or activity may be a new avenue for altering T cell function and treating immune dyscrasias.

Figure 1. B-1 cells secrete protective natural antibody

B-1 and B-2 cells fulfill different functions in generating serological immunity as shown in the right and left panels. B-2 cells express immunoglobulin molecules that are junctionally diverse as a result of N-region addition. Following antigen/microbial/vaccination activation, B-2 cells undergo multiple steps to produce antibody secreting cells that require substantial periods of time to develop after initial exposure. Specific B-2 cells that bind antigen are selected to develop germinal centers during which marked B cell expansion is accompanied by somatic hypermutation (and isotype switching), resulting in further repertoire diversity and selection on the basis of antigen-binding affinity. Differentiation to antibody secreting plasma cells (and memory B cells) completes the process. In contrast, B-1 cells express immunoglobulin molecules that are less diverse as a result of minimal N-region addition and minimal somatic hypermutation. Although many B-1 cell antibodies manifest modest affinity, they are often polyreactive, and the latter feature may assist in functional efficacy. B-1 cells constitutively and spontaneously secrete the range of antibodies (mostly IgM) they express, without the need for stimulation or activation (although immunoglobulin secretion may be increased by certain TLR agonists). This “natural” antibody constitutes the bulk of normal baseline or resting IgM. The B-1 cell repertoire represents a pre-existing anti-microbial shield and functions to dispose of cellular debris and toxic molecules. Because B-1 cell antibodies closely mirror germline sequences, the B-1 cell repertoire is considered to have been optimized for survival over evolutionary time. Thus B-1 cell antibodies are selected for function whereas B-2 cell antibodies are selected for affinity. Erosion of the natural antibody repertoire with increasing age may underlie susceptibility of older individuals to certain infectious and degenerative diseases. Because B-1 cell antibodies are often autoreactive, imposition of somatic hypermutation and isotype switching could result in production of typical pathogenic autoantibodies.

Figure 2

Chronically signaling B-1 cells stimulate and regulate T cell responses. B-1 cells affect immune system function in several ways beyond antibody production. B-1 cells strongly present antigen and stimulate T cell proliferation, which depends on baseline enhanced expression of CD86, absent any stimulation or activation. Upregulated CD86 in turn depends on chronic signaling that is presumably generated by B cell receptor binding to self-antigen, but could represent antigen independent activity. Further, B-1 cells promote CD4 T cell differentiation to pro-inflammatory IL-17-containing Th17 cells, a process that also depends on CD86. Whereas these activities promote inflammation, B-1 cells also produce and secrete immunosuppressive IL-10. Thus, B-1 cells manifest a full suite of immune system modulatory activities that include T cell expansion, inflammation, and immunosuppression. As such, B-1 cells express countervailing activities, the balance of which may regulate the direction of normal T cell immune responses and, under pathologic conditions, may contribute to autoimmunity.