Specificity for the tumor-associated self-antigen WT1 drives the development of fully functional memory T cells in the absence of vaccination

• Published in: Blood Vol. 117; no. 25; pp. 6813 - 6824
• Main Authors: Pospori, Constandina, Xue, Shao-An, Holler, Angelika, Voisine, Cecile, Perro, Mario, King, Judith, Fallah-Arani, Farnaz, Flutter, Barry, Chakraverty, Ronjon, Stauss, Hans J., Morris, Emma C.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 23.06.2011; Americain Society of Hematology
• Subjects: Animals; Biological and medical sciences; Cell Line; Gene Expression; Gene Transfer Techniques; Hematologic and hematopoietic diseases; Humans; Immunologic Memory; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Stem Cells - immunology; Stem Cells - metabolism; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Thymus Gland - immunology; Vaccination; Wilms Tumor - immunology; WT1 Proteins - genetics; WT1 Proteins - immunology; Prevention; Specificity; Tumor associated antigen; Hematology; Vaccination; T-Lymphocyte; Wilms tumor gene; Tumor suppressor gene; Memory lymphocyte
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-08-304568

Recently, vaccines against the Wilms Tumor antigen 1 (WT1) have been tested in cancer patients. However, it is currently not known whether physiologic levels of WT1 expression in stem and progenitor cells of normal tissue result in the deletion or tolerance induction of WT1-specific T cells. Here, we used an human leukocyte antigen-transgenic murine model to study the fate of human leukocyte antigen class-I restricted, WT1-specific T cells in the thymus and in the periphery. Thymocytes expressing a WT1-specific T-cell receptor derived from high avidity human CD8 T cells were positively selected into the single-positive CD8 population. In the periphery, T cells specific for the WT1 antigen differentiated into CD44-high memory phenotype cells, whereas T cells specific for a non–self-viral antigen retained a CD44low naive phenotype. Only the WT1-specific T cells, but not the virus-specific T cells, displayed rapid antigen-specific effector function without prior vaccination. Despite long-term persistence of WT1-specific memory T cells, the animals did not develop autoimmunity, and the function of hematopoietic stem and progenitor cells was unimpaired. This is the first demonstration that specificity for a tumor-associated self-antigen may drive differentiation of functionally competent memory T cells.