Autoimmunity and tumor immunity induced by immune responses to mutations in self

Nature Medicine 12:198-206, 2006

Speaker：王瑋祥                             Time：2006/03/08, 15:10~16:00

Commentator：翁舷誌 老師                   Place：Room 601

Abstract：

Adaptive immune system can recognize and respond to changes in genomic integrity. Mutations, which may accumulate with aging and with chronic inflammation, have the potential to contribute to the pathogenesis of diseases such as cancer. However, the immune system must be balanced to avoid autoimmunity. In this paper, the authors used an error-prone polymerase chain reaction to generate two randomly mutated libraries, tyrosinase-related protein 1 (Tyrp1) and dopachrome tautomerase (Dct), which are expressed in melanocytes. First, they found that using themutated libraries as DNA vaccine can elicit B16F10LM3 melanoma tumor rejection and autoimmunity hypopigmentation. Second, they used MHC–deficient and T-cell depleted mice to prove thatCD4⁺ and CD8⁺ T cells are required for immunity induced by mutated libraries, but CD4⁺ cells are not required at the effector phase, and even MHC allelic restriction can be surmounted bymutated libraries. Third, they selected mutated clones and characterized them. On the beginning, they demonstrated that the truncations were sufficient to induce autoimmunity by Dct^TR-382, a wild-type Dct with a premature stop codon at position 382 corresponding to Dct^M1, which elicited both tumor immunity and autoimmunity. Same results can be seen in truncated wild-type Dct^TR-30containing a start codon corresponding to Dct^M2, which induced autoimmunity but not tumor immunity. Furthermore, they found that the immunogenicity of the mutated Dct clones was not explained simply by increased or decreased protein instability. On the other hand, mutant Dct^M1 is processed by endosomal proteases, whereas Dct^M2 is processed in the cytosol by proteasomes. This phenomenon differs from wild-type Dct. They also observed deficient maturation of mutated Dct glycoproteins, consistent with a lack of movement through the Golgi for carbohydrate processing. Finally, the authors showed that Dct^TR-382 was sufficient for inducing CD8⁺ T-cell responses to Dct(363–371) that consistent with the altered cellular fate of Dct^M1, which facilitated antigen processing and presented an immunogenic cryptic epitope. Besides, a mutation in Dct^M1 created an MHC class II–restricted neoepitope that generated CD4⁺ T helper cells. According to these results, mutations that lead to recognition of mutated epitopes presented only by cancer cells without cross-recognition of the corresponding native epitopes may be particularly important for cancer immunity. The strategy of mutated DNA vaccines has the potential to address limitations of vaccination against cancer and infectious pathogens by generating broad repertoires of altered antigens.

References：

1. Engelhorn ME. et al. Autoimmunity and tumor immunity induced by immune responses to mutations in self. Nat. Med. 12:198-206, 2006.

2. Dyall, R. et al. Heteroclitic immunization induces tumor immunity. J. Exp. Med. 188:1553-1561, 1998.