Effect of interleukin-15 on effector and regulatory function of anti-CD3/ anti-CD28-stimulated CD4⁺ T cells

Autologous transfer of anti-CD3/anti-CD28 (CD3/CD28)-activated CD4⁺ T cells may benefit patients receiving autologous stem cell transplant with severe CD4 lymphopenia. Interleukin (IL)-15, an IL-2-like cytokine that promotes T cell survival may enhance immune reconstitution in conjunction with adoptive immunotherapy. We investigated the effect of IL-15 on effector and regulatory function of CD3/CD28-activated CD4⁺ T cells. IL-15 upregulated CD45RO and CD25 whereas it downregulated CD62L expression of CD3/CD28-stimulated CD4⁺ T cells. Both type 1 (IFN-γ, tumor necrosis factor (TNF)-α) and type 2 (IL-5 and IL-10) production by CD3/ CD28-activated CD4⁺ T cells was further enhanced by IL-15. Co-culture experiments revealed that CD3/CD28-activated CD4⁺ T cells downregulated proliferation of autologous peripheral blood lymphocytes (PBLs) and CD8⁺ PBL subsets upon TCR ligation, a contact-dependent effect that was further enhanced by pretreatment with IL-15. Flow cytometric analysis of cell mixture with carboxyfluorescein diacetate succinimidyl ester and Annexin-V-PE staining revealed that CD3/ CD28+IL-15-activated CD4⁺ T cells showed increased apoptosis over CD4⁺ T cells stimulated with CD3/CD28 alone. Taken together, pretreatment of CD3/CD28-activated CD4⁺ T cells with IL-15 may increase regulatory function but may aggravate activation-induced apoptosis of CD3/CD28 CD4⁺ T cells.