IL-2 Simultaneously Expands Foxp3+ T Regulatory and T Effector Cells and Confers Resistance to Severe Tuberculosis (TB): Implicative Treg–T Effector Cooperation in Immunity to TB

Abstract

The possibility that simultaneous expansion of T regulatory cells (Treg) and T effector cells early postinfection can confer some immunological benefits has not been studied. In this study, we tested the hypothesis that early, simultaneous cytokine expansion of Treg and T effector cells in a tissue infection site can allow these T cell populations to act in concert to control tissue inflammation/damage while containing infection. IL-2 treatments early after Mycobacterium tuberculosis infection of macaques induced simultaneous expansion of CD4⁺CD25⁺Foxp3⁺ Treg, CD8⁺CD25⁺Foxp3⁺ T cells, and CD4⁺ T effector/CD8⁺ T effector/Vγ2Vδ2 T effector populations producing anti-M. tuberculosis cytokines IFN-γ and perforin, and conferred resistance to severe TB inflammation and lesions. IL-2–expanded Foxp3⁺ Treg readily accumulated in pulmonary compartment, but despite this, rapid pulmonary trafficking/accumulation of IL-2–activated T effector populations still occurred. Such simultaneous recruitments of IL-2–expanded Treg and T effector populations to pulmonary compartment during M. tuberculosis infection correlated with IL-2–induced resistance to TB lesions without causing Treg-associated increases in M. tuberculosis burdens. In vivo depletion of IL-2–expanded CD4⁺Foxp3⁺ Treg and CD4⁺ T effectors during IL-2 treatment of M. tuberculosis-infected macaques significantly reduced IL-2–induced resistance to TB lesions, suggesting that IL-2–expanded CD4⁺ T effector cells and Treg contributed to anti-TB immunity. Thus, IL-2 can simultaneously activate and expand T effector cells and Foxp3⁺ Treg populations and confer resistance to severe TB without enhancing M. tuberculosis infection.