CD4+ T cell responses to self- and mutated p53 determinants during tumorigenesis in mice.
We analyzed CD4+ T helper responses to wild-type (wt) and mutated (mut) p53 protein in normal and tumor-bearing mice. In normal mice, we observed that although some self-p53 determinants induced negative selection of p53-reactive CD4+ T cells, other p53 determinants (cryptic) were immunogenic. Next, BALB/c mice were inoculated with J774 syngeneic tumor cell line expressing mut p53. BALB/c tumor-bearing mice mounted potent CD4+ T cell responses to two formerly cryptic peptides on self-p53. This response was characterized by massive production of IL-5, a Th2-type lymphokine. Interestingly, we found that T cell response was induced by different p53 peptides depending upon the stage of cancer. Mut p53 gene was shown to contain a single mutation resulting in the substitution of a tyrosine by a histidine at position 231 of the protein. Two peptides corresponding to wt and mutated sequences of this region were synthesized. Both peptides bound to the MHC class II-presenting molecule (Ed) with similar affinities. However, only mut p53.225-239 induced T cell responses in normal BALB/c mice, a result strongly suggesting that high-affinity wt p53.225-239 autoreactive T cells had been eliminated in these mice. Surprisingly, CD4+ T cell responses to both mut and wt p53.225-239 peptides were recorded in J774 tumor-bearing mice, a phenomenon attributed to the recruitment of low-avidity p53.225-239 self-reactive T cells.
Fedoseyeva
E V
EV
Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California, San Francisco, CA 94143, USA.
Boisgérault
F
F
Anosova
N G
NG
Wollish
W S
WS
Arlotta
P
P
Jensen
P E
PE
Ono
S J
SJ
Benichou
G
G
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000302:isolation & purification; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D012513:Sarcoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism
D018076:DNA, Complementary; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53