Role of common gamma chain utilizing cytokines for immune reconstitution in HIV infection

Many cytokines that utilize the common gamma (Cgamma) chain signaling pathway, viz Interleukin (IL)-2, IL-15, and IL-7 are known to be important for inducing T cell maturation, proliferation, or survival. Untreated chronic HIV infection is associated with profound quantitative and qualitative deficiency of CD4 T cells, which is partially reversed following highly active antiretroviral therapy (HAART). A subset of patients, however, fail to recover CD4 T cells despite virologic suppression. The role of Cgamma chain cytokines in influencing immune reconstitution following potent antiretroviral therapy is discussed. Maturation markers (naïve, central memory, effector memory, and effector), cytokine receptors IL-2Rbeta, Cgamma chain, IL-7Ralpha, IL-15Ralpha, and cytokine-induced proliferative responses of T cells in a cohort of HIV-infected pediatric patients and adults classified on the basis of immunologic and virologic response to antiretroviral therapy were examined. The studies indicated that patients had increased percentages of effector memory CD8+ T cells in comparison to healthy volunteers. While patients with partially controlled viremia and poor CD4 T cell reconstitution manifested poor proliferative responses to anti-CD3 or HIV gag antigen stimulation, proliferative responses to Cgamma chain utilizing cytokines IL-2, IL-7, and IL-15 were robust. Another Cgamma chain utilizing cytokine, IL-21 had no influence on cellular proliferation but enhanced perforin expression in effector CD8 T cells. Thus, cytokine receptor deficiencies may contribute to immune deficiency in HIV-infected patients, and Cgamma chain cytokines may play an important role in vivo in immune homeostasis in lymphopenic patients by maintaining the memory subsets of T cells in patients with CD4 T cell deficiency.