(A) CD8⁺ Tregs inhibit expansion of CD4⁺ T cells. (i) CD8⁺ Tregs form NOX2-enriched synapses at the plasma membrane. (ii) NOX2-containing microvesicles form and are (iii) delivered to target CD4⁺ T cells. (iv) This leads to increased ROS in the target cells, (v) which mediates reduction of ZAP70 phosphorylation and (vi) inhibition of TCR signaling. Teff, effector T cell. (B) The capacity of CD8⁺ Tregs to produce NOX2 declines with age. This loss of CD8⁺ Treg functionality may facilitate the expansion of potentially autoreactive CD4⁺ T cells. As proof of this concept, Wen et al. observed a prominent loss of CD8⁺ Treg function in patients suffering from GCA, a CD4⁺ T cell–mediated disease. These observations raise a series of interesting questions. What is the role of CD8⁺ Tregs in other age-associated autoimmune conditions, such as late-onset rheumatoid arthritis (LORA), in chronic infections, and in vaccine responses? How is CD8⁺ Treg function affected in individuals with genetic NOX2 deficiency, such as those with CGD? Finally, what impact does the loss of CD8⁺ Treg function have on CD4⁺ Treg and/or Th subset compartments?