• Akt2 regulates interferon type 1 responses.• Akt2-/- mice have reduced mortality in response to viral infection but aggravates the severity of SLE.• Deficiency of Akt2 promotes anti-inflammatory macrophages.• Akt2 regulates ROS production and migration of DC• Akt2 promotes differentiation of CD8+ T cells. Here, CD8A is linked to systemic lupus erythematosus.