Transforming growth factor β1 (TGF-β1) suppresses growth of B-cell lymphoma cells by p14(ARF)-dependent regulation of mutant p53.

Previously we reported that TGF-β1-induced growth suppression was associated with a decrease in mutant p53 levels in B-cell lymphoma cells. The goal of the present study was to understand the mechanism involved in TGF-β1-mediated down-regulation of mutant p53. In RL and CA46, two B-cell lymphoma cell lines, TGF-β1 treatment caused down-regulation of E2F-1 transcription factor resulting in the down-regulation of both p14(ARF) and mutant p53, leading to growth arrest.

Dual isotype expressing B cells [kappa(+)/lambda(+)] arise during the ontogeny of B cells in the bone marrow of normal nontransgenic mice.

Central to the clonal selection theory is the tenet that a single B cell expresses a single receptor with a single specificity. Previously, based on our work in anti-phosphocholine transgenic mouse models, we suggested that B cells escaped clonal deletion by coexpression of more than one receptor on their cell surface. We argued that "receptor dilution" was necessary when: (i) the expressed immunoglobulin receptor is essential for immune protection against pathogens and (ii) this protective receptor is autoreactive and would be clonally deleted, leaving a hole in the B cell repertoire.

2 BCR or NOT 2 BCR - receptor dilution: a unique mechanism for preventing the development of holes in the protective B cell repertoire.

The clonal selection theory and the associated corollaries have had a major influence in shaping our thinking about lymphoid cell development as well as how these cells respond to antigenic challenges. Among these concepts are that a single B cell expresses a single receptor with a single antigen specificity. While these hypotheses have proven invaluable in expanding our understanding of immune response, over time numerous observations have been made that suggest that the single cell, single receptor, single specificity model is not absolute.

The M603 idiotype is lost in the response to phosphocholine in terminal deoxynucleotidyl transferase-deficient mice.

The majority of anti-phosphocholine (PC) antibodies induced by the PC epitope in Proteus morganii (PM) express the M603 idiotype (id), which is characterized by an invariant Asp to Asn substitution at the V(H):D(H) junction. To elucidate the molecular basis by which M603-like B cells acquire the mutations resulting in this invariant substitution, we analyzed the immune response to PC-PM in terminal deoxynucleotidyl transferase (TdT) gene knockout (KO) mice. In the absence of TdT, T15-id antibodies comprised 80-100% of the primary response to PC-PM.

T15-idiotype-negative B cells dominate the phosphocholine binding cells in the preimmune repertoire of T15i knockin mice.

T15i knockin (KI) mice express a H chain that is encoded by a rearranged T15 VDJ transgene which has been inserted into the J(H) region of chromosome 12. This T15H chain combines with a kappa22-33 L chain to produce a T15-Id+ Ab having specificity for phosphocholine (PC). Inasmuch as T15-Id+ Abs dominate the primary immune response to PC in normal mice, it was surprising to find that 80% of the PC-dextran-binding B cells in unimmunized homozygous T15i KI mice were T15-Id-.