Loss of ATG5 impairs CD4+ T cell activation and promotes anti-tumor responses

Macroautophagy (hereafter called autophagy) is an ancient catabolic process that delivers bulky cargo to lysosomal degradation. The autophagic pathway is regulated by autophagy-related (ATG) proteins that govern the formation of double-membraned vesicles called autophagosomes. Autophagy has been shown to be important for T cell survival and proliferation. However, all studies performed so far used genetic models, in which deletion of an essential <i>Atg</i> gene occurs at early stages of thymic T cell development, raising the question whether developmental defects account for the phenotypes observed in mature T cells. Especially regarding CD4⁺ T helper cells, little is known about the function of autophagy in specific subsets. Therefore, we generated mice that lack <i>Atg5</i>, an essential component of the core autophagy machinery, in activated CD4⁺ T cells using OX40-Cre mice. As expected, thymic T cell development was unaffected in these mice. Despite impaired CD4⁺ T cell activation, Atg5^ΔOX40 mice developed lymphadenopathy and exhibited increased T cell numbers, pointing to a defect in immune regulation. Accordingly, frequencies of Foxp3⁺ regulatory T (Treg) cells were decreased. While activation-induced cell death and <i>in vitro</i> suppressive activity of Treg cells were not affected, ATG5 deficiency in CD4⁺ T cells led to increased anti-tumor responses against melanoma. In conclusion, our data suggest that ATG5 is crucial for the functional properties of CD4⁺ T cells and the homeostasis of Treg cells.