CD4+ T cell activation and tolerance induction in B cell knockout mice.

Abstract

SummaryB cell knockout mice p, MT/p, MT were used to examine the requirement for B cell antigen (Ag) presentation in the establishment of CD4 + T cell tolerance. CD4 + T cells from p, MT mice injected with exogenous protein Ag in adjuvant responded to in vitro challenge by transcription of cytokine mKNA, cytokine secretion, and proliferation. Peripheral tolerance could be established in p~MT mice with a single dose of deaggragated protein. This tolerance was manifested by a loss of T cell proliferation and cytokine production (including both T helper cell type 1 [Thl]-and Th2-related cytokines), indicating that B cells are not required for the induction of peripheral T cell tolerance and suggesting that the dual zone tolerance theory is not applicable to all protein Ags and is not mediated through Ag presentation by B cells.T he role of B cells in Ag presentation to peripheral CD4 + T cell responses is controversial. Although B cells are the most abundant MHC class II-positive cell and have been shown in some studies to be involved in the activation of peripheral T cells, other investigators have argued against the notion that B cells are necessary as APCs for induction of T cell responses. Thus, results from studies have ranged from, first, the B cell as the crucial initiating APC in the lymph node (1), through second, the B cell as a necessary mediator of T cell clonal expansion and secondary proliferation (2-5), to third, normal priming and proliferation of T cells in the absence of B cells (6, 7). These studies all examined Ag-specific T cell activation in mice that had been rendered deficient in B cells, either by continuous injection of anti-p, Ab, by reconstitution of SCID mice with naive T cells, or, most recently, by targeted deletion of either the IgM heavy chain gene (8) or the JH gene segment (5, 9). The role of B cells in the induction of peripheral T cell tolerance is less controversial. B cells can serve as APCs in the induction of Ag-specific tolerance in naive CD4 + and CD8 + T cells (10, 11) and in Ag-specific T cell clones (12). These reports led to speculation by investigators that tolerance induction in virgin T cells is a primary function of the B cell.To reevaluate the role of B cells as APCs for activation and tolerization ofCD4 + T cells, we used the B cell knockout mouse ~MT/p~MT (hereafter p~MT), which was generated by introduction of a nonsense mutation into the transmembrane exon of the IgM heavy chain gene, resulting in a total deletion of B cells (13). The Ag used to investigate CD4 + T cell responses in these mice was human ~/-globulin (HGG), 1 which is a T-dependent Ag able to induce either tolerance or activation ofT cells, depending on the injection procedure. HGG injected subcutaneously in adjuvant induces T cell proliferation and cytokine secretion as well as a significant anti-HGG Ag response, whereas a single injection of deaggregated HGG (DHGG) induces a long-lasting peripheral tolerance that affects both B cells and T cells (reviewed in 14 and 15). In the case ofT cells, ...

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