There is increasing interest in the chronic lymphocytic leukemia (CLL) microenvironment and the mechanisms that may promote CLL cell survival and proliferation. A role for T helper (Th) cells has been suggested, but current evidence is only circumstantial. Here we show that CLL patients had memory Th cells that were specific for endogenous CLL antigens. These Th cells activated autologous CLL cell proliferation in vitro and in human → mouse xenograft experiments. Moreover, CLL cells were efficient antigen-presenting cells that could endocytose and process complex proteins through antigen uptake pathways, including the B cell receptor. Activation of CLL cells by Th cells was contact and CD40L dependent. The results suggest that CLL is driven by ongoing immune responses related to Th cell-CLL cell interaction. We propose that Th cells support malignant B cells and that they could be targeted in the treatment of CLL.

B cells spontaneously process their endogenous Ig and present V region peptides on their MHC class II molecules. We have here investigated whether B cells collaborate with V region-specific CD4+ T cells in vivo. By use of paired Ig L chain-transgenic and TCR-transgenic mice and cell transfer into normal hosts, we demonstrate that B cell presentation of a VL region peptide to CD4+ T cells results in germinal centers, plasma cells, and Ab secretion. Because the transgenic B cells have a fixed L chain but polyclonal H chains, their B cell receptor (BCR) repertoire is diverse and may bind a multitude of ligands. In a hapten-based system, BCR ligation concomitant with V region-driven T-B collaboration induced germinal center formation and an IgM → IgG isotype switch. In the absence of BCR ligation, mainly IgM was produced. Consistent with this, prolonged V region-driven T-B collaboration resulted in high titers of IgG autoantibodies against ubiquitous self-Ags, while natural-type Abs against exotic bacteria remained IgM. Taken together, V region-driven T-B collaboration may explain induction of natural IgM Abs (absence of BCR ligation) and IgG autoantibodies (BCR ligation by autoantigen) and may be involved in the development of autoimmunity.

B cells present BCR V region-derived Id-peptides on their MHC class II molecules to Id-specific CD4+ T cells. Prolonged Id-driven T-B collaboration could cause autoimmune disease, but this possibility is difficult to test in normal individuals. We have investigated whether mice doubly transgenic for an Id+ Ig L chain and an Id-specific TCR develop autoimmune disease. Surprisingly, T cell tolerance was not complete in these mice because a low frequency of weakly Id-reactive CD4+ T cells accumulated with age. These escapee Id-specific T cells provided chronic help for Id+ B cells, resulting in a lethal systemic autoimmune disease including germinal center reactions, hypergammaglobulinemia, IgG autoantibodies, glomerulonephritis, arthritis, skin affection, and inflammatory bowel disease. Inflamed tissues contained foci of Id-driven T-B collaboration, with deposition of IgG and complement. The disease could be transferred with B and T cells. The results demonstrate a novel mechanism for development of autoimmune disease in which self-reactive Id+ B cells receive prolonged help from Id-specific T cells, thus bypassing the need for help from T cells recognizing conventional Ag.