Germinal center formation, immunoglobulin class switching, and autoantibody production driven by "non α/β" T cells

Abstract

The production of class-switched antibodies, particularly immunoglobulin (Ig)G1 and IgE, occurs efficiently in T cell receptor (TCR)α-/- mice that are congenitally devoid of α/β T cells. This finding runs counter to a wealth of data indicating that IgG1 and IgE synthesis are largely dependent on the collaboration between B and α/β T cells. Furthermore, many of the antibodies synthesized in TCRα-/- mice are reactive to a similar spectrum of self-antigens as that targeted by autoantibodies characterizing human systemic lupus erythematosus (SLE). SLE, too, is most commonly regarded as an α/β T cell-mediated condition. To distinguish whether the development of autoantibodies in TCRα-/- mice is due to an intrinsic de-regulation of B cells, or to a heretofore poorly characterized collaboration between B and "non-α/β T" cells, the phenotype has been reconstituted by transfer of various populations of B and non-α/β T cells including cloned γ/δ T cells derived from TCRα-/- mice, to severe combined immunodeficient (SCID) mice. The results establish that the reproducible production of IgG1 (including autoantibodies) is a product of non-α/β T cell help that can be provided by γ/δ T cells. This type of B-T collaboration sustains the production of germinal centers, lymphoid follicles that ordinarily are anatomical signatures of α/β T-B cell collaboration. Thus, non-α/β T cell help may drive Ig synthesis and autoreactivity under various circumstances, especially in cases of α/β T cell immunodeficiency.