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High Accumulation of T Regulatory Cells Prevents the Activation of Immune Responses in Aged Animals¹

Sidney Kimmel Cancer Center, San Diego, CA 92121

In our previous in vivo study we demonstrated that young BALB/c mice effectively rejected the BM-185 tumor cells expressing enhanced GFP (EGFP) as a surrogate tumor Ag. In contrast, old BALB/c mice succumbed to the BM-185-EGFP tumors, indicating that there is a deficiency in old animals preventing the rejection of immunogenic tumors. There is cumulative evidence indicating that regulatory T (T_reg) cells control the activation of primary and memory T cell responses. However, very little is known about whether there is a relation between T_regs and the lack of immune responses in the aged. We evaluated young and aged animals, and our results demonstrated that there are significantly more CD4⁺CD25⁺FoxP3⁺ and CD8⁺CD25⁺FoxP3⁺ T_regs in the spleen and lymph nodes of old animals when compared with the young. Depletion of CD25⁺ cells with anti-CD25 mAb induces the rejection of BM-185-EGFP cells, restores antitumor T cell cytotoxic activity, and results in the generation of a protective memory response against the BM-185 wild-type tumors in old mice. Furthermore, vaccination with CpG-oligodeoxynucleotide decreases the number of T_reg cells in old animals to the same levels as young mice, restoring the primary and memory antitumor immune responses against BM-185-EGFP tumors. Taken together, these results indicate that there is a direct correlation between the expansion of T_reg cells and immune deficiency in the old, and that depletion of these cells might be critical for restoring immune responses in aged animals.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant CA 78579 (to J.L.) from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Joseph Lustgarten, Cancer Center Scottsdale, Mayo Clinic Arizona, Johnson Research Building 3-356, 13400 East Shea Boulevard, Scottsdale, AZ 85259. E-mail address: lustgarten.joseph{at}mayo.edu

³ Abbreviations used in this paper: EGFP, enhanced GFP; ODN, oligodeoxynucleotide; T_reg, regulatory T; w.t., wild type.