Homeostatic cytokines induce CD4 downregulation in African green monkeys Independently of antigen exposure to generate simian immunodeficiency Virus-Resistant CD8αα T cells

African green monkeys (AGMs; genus Chlorocebus) are a natural host of simian immunodeficiency virus (SIV_AGM). As they do not develop simian AIDS, there is great interest in understanding how this species has evolved to avoid immunodeficiency. Adult African green monkeys naturally have low numbers of CD4⁺ T cells and a large population of major histocompatibility complex class II-restricted CD8α^dim T cells that are generated through CD4 downregulation in CD4⁺ T cells. Mechanisms that drive this process of CD4 downregulation are unknown. Here, we show that juvenile AGMs accelerate CD4-to-CD8αα conversion upon SIV infection and avoid progression to AIDS. The CD4 downregulation induced by SIV infection is not limited to SIV-specific T cells, and vaccination of an adult AGM who had a negligible number of CD4 T cells demonstrated that CD4 downregulation can occur without antigenic exposure. Finally, we show that the T cell homeostatic cytokines interleukin-2 (IL-2), IL-7, and IL-15 can induce CD4 downregulation in vitro. These data identify a mechanism that allows AGMs to generate a large, diverse population of T cells that perform CD4 T cell functions but are resistant to SIV infection. A better understanding of this mechanism may allow the development of treatments to induce protective CD4 downregulation in humans.