HUMAN EXTRACELLULAR PROTEINS DISPLAY A DIFFERENT PATTERN OF LOCAL SEQUENCE SIMILARITY WITH THE 4 CLASSES OF HUMAN T-CELL RECEPTOR-V REGIONSTHAN FOREIGN PROTEINS AND HUMAN INTRACELLULAR PROTEINS - A PRELIMINARY-REPORT

A pool of 110 randomly selected/generated amino acids sequences was us ed to perform specific local sequence similarity alignment analysis wi th the pool of 279 reported sequences of human T-cell receptor (TCR) V -regions. The 110 analyzed sequences were divided, according to their origin and nature, into six protein groups, as: human intracellular (h i), extracellular/transmembrane (he) and extracellular adhesive matrix (ha) proteins, 'average' human proteins (hum), proteins of non-human origin (nhum) and randomly generated quasi-protein sequences (r). Thes e sequences were decomposed into all their overlapping 11-mer segments , generating a total of 56 836 derived peptides (at least 8000 per gro up). Each derived peptide was aligned with the 279 human TCR V-regions and assigned to the category (alpha-like, beta-like, gamma-like or de lta-like) corresponding to the class (V alpha, V beta, V gamma or V de lta) of the V-region encompassing the most similar segment, as determi ned by the performed similarity-search. The six protein groups were fo und to differ significantly in their distribution of derived peptides among the four categories. According to the binomial tests results, hu man proteins from the extracellular compartment (he, ha) comprise a hi gher proportion of delta-like segments (P = 2.3 x 10(-2) and P < 10(-8 ), respectively) than the 'average' human proteins (hum). In addition, and in accordance with this finding, proteins that are normally not f ound in that topological compartment comprise a lower proportion of de lta-like peptides (P = 1.4 x 10(-5) and P < 10(-8) for groups nhum and hi, respectively) than the 'average' human proteins (hum). In contras t, these proteins comprise a higher proportion of gamma-like segments (P = 8.3 x 10(-3), P = 1.4 x 10(-3) and P = 1.7 x 10(-4), for groups r , nhum and hi, respectively) than the 'average' human proteins (hum). These findings indicate significant differences between proteins encou ntered in the extracellular compartment-that are normally immunologica lly tolerated-and those the presence of which is usually non-tolerated . The results suggest that the discrimination and the reaction of the human immune network to proteins found in the extracellular compartmen t correlate with the proteins' pattern of preferential local sequence similarity with the V gamma and V delta classes of human TCR V-regions , implying a specific and an important role of gamma delta-cells in th e maintenance of the immune homeostasis. Whether this implication repr esents a rule associated with self-tolerance, will be investigated by future analyses. (C) 1998 Elsevier Science B.V. All rights reserved.