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CD4⁺ T Cell Responses to Self- and Mutated p53 Determinants During Tumorigenesis in Mice¹

Eugenia V. Fedoseyeva^2,*, Florence Boisgérault^2,*, Natalie G. Anosova^2,*, Wendy S. Wollish^*, Paola Arlotta, Peter E. Jensen, Santa J. Ono and Gilles Benichou^3,*

^* Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California, San Francisco, CA 94143; Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114; and Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322

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 (E^d) 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.

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