A hypothesis accounting for the paradoxical expression of the D gene segmentin the BCR and the TCR

Abstract

The D gene segment expressed in both the TCR and BCR has a challenging behavior that begs interpretation. It is incorporated in three reading frames in the rearranged transcription unit but is expressed in antigen-selected cells in a preferred frame. Why was it so important to waste 2/3 of newborn cells? The hypothesis is presented that the D region is framework playing a role in both the TCR and the BCR by determining whether a signal is transmitted to the cell upon interaction with a cognate ligand. This assumption operates in determining haplotype exclusion for the BCR and in regulating the signaling orientation for the TCR. Relevant data as well as a definitive experiment challenging the validity of this hypothesis, are discussed.

Partial versus Productive Immunoglobulin Heavy Locus Rearrangements in Chronic Lymphocytic Leukemia: Implications for B-Cell Receptor Stereotypy

“…In most previous mouse studies, the preferred (that is, hydrophilic) RF is designated as RF1, whereas a far more sensible procedure is followed in the human, first proposed by Kabat's group, and adopted by IMGT, with RF1 counting from the first nucleotide of the D-REGION in germline configuration (that follows the 5′-HEPTAMER), thus defining three consecutively numbered "logical" RF (1,16,43). Hence, every IGHD gene has only one preferred RF, and this RF is not the same for all IGHD genes.…”

“…The biological mechanism, which determines whether a partial IGHD-IGHJ rearrangement will develop into an IGHV-IGHD-IGHJ rearrangement is still unknown. Studies in the mouse have shown a biased usage of IGHD genes in reading frames (RFs) encoding for hydrophilic amino acids in IGHV-IGHD-IGHJ rearrangements (V-D-J) along with counter-selection of IGHD-IGHJ rearrangements with IGHD genes in RF encoding for hydrophobic amino acids or stop codons (13)(14)(15)(16)(17)(18) . Relevant studies have also shown that IGHD-IGHJ with IGHD genes rearranged in RF encoding for hydrophobic amino acids can be translated into a truncated μ protein, called Dμ (13,19).…”

What is so special about thinking; after all, we all do it!

“…Making sense of its structure is what makes it so intriguing. I have dealt with this in detail elsewhere (Cohn, 2008a). Here, I would like to highlight the enigma and call upon the clairvoyant among you to give us the answer.…”

“…My hypothesis (Cohn, 2008a) and the only validly competing proposal, that of Schroeder (Schroeder et al, 1998) are discussed where referenced.…”

Ten experiments that would make a difference in understanding immune mechanisms

“…One assumption is that it regulates the transmission of Signal 1. In the B-cell the non-signaling D H RFs would contribute to haplotype exclusion; in the T-cell the D b RF would determine the signaling orientation of the interaction with ligand, restrictive or alloreactive (see Hypothesis I) [25].…”