The heat-shock response and intracellular self/not-self discrimination  

At previous conferences I presented evidence for the hypothesis that the crowded cytosol constitutes an environment supporting the presentation to T-cells, as MHC-peptide complexes, of peptides from normal, rather than mutated, intracellular self proteins (Cell Stress & Chaperones 1999, 4:205; 2000, 5:375; J. Theor. Biol. 2001, 210:425; Trends Immunol. 2002, 23:575). At the fourth conference, some of the evidence that has appeared in the interim will be reviewed. For example, 

(1) the enigmatic minor histocompatability antigens correspond to "peptides from naturally processed intracellular proteins that can be encoded by - - autosomal chromosomes." It is proposed that "T cells specific for the malignancy-associated minor H antigens are preferentially generated against products of polymorphic proteins that are either overexpressed in malignancy or are expressed as a result of the malignancy" (Trends Immunol. 2004, 25:56). 

(2) It is becoming increasingly recognized that "T cells are not tolerant of every self peptide in the organism - - and - -a protein can be expressed at a substantial level yet remain below the threshold of T cell detection. Should a peptide from such a protein finally become exposed to CD8+ T cells as a result of the intracellular stress response, it may be recognized as foreign" (Immunity 2003, 19:469). 

(3) The paraneoplastic syndromes (New Eng. J. Med. 2003, 349:1543), and the appearance of autoimmune vitiligo when melanoma-bearing animals are traumatized (Cancer Res. 2004, 64:1509), all support this. 

(4) A paper, kindly drawn to my attention by Jan Peczkis, reads: "Our results thus extend the possible sources of tumor antigen coding sequences to 'junk' DNA and seriously raise the possibility that any DNA sequence can lead to antigen production, the only limitation being that it must be transcribed" (J. Exp. Med . 2000, 191:1617). 

    We have proposed that when cells are stressed (e.g. pathogen, tumor, heat-shock), junk DNA is transcribed from the "hidden transcriptome," by run-on transcription of normal genes and Alu repetitive elements. The RNA so formed may form dsRNA, so activating intracellular alarms, or be translated to generate proteins from which peptides are derived. Stress-induced transcription of a particular transcript at a critical developmental stage could produce "phenocopies" (Goldschmidt) not reflective of the genotype that is normally selectively expressed in a particular tissue. For further background please see [these web-pages].