Anti‐tumor immune response induced by homeostatic proliferation and CD28 signaling

Abstract

Recent studies suggested that homeostatic proliferation (HP) could lead immune response against tumor‐associated antigen (TAA) resulting in rejection of tumor. Although there has been little evidence suggesting any requirement for co‐stimulatory signal and IL‐2 for the expansion and phenotypical changes of naive T cells in various models of lymphopenic host, we demonstrate that CD28 signaling is indispensable for the differentiation of donor CD8+ T cells into functional CTL during HP. Administration of IL‐2 on early time points i.e. day 0 to 5 of HP could not enhance the anti‐tumor effects, however, the tumor specific immune response induced by HP was significantly enhanced when IL‐2 was administrated systemically at 10 to 15 days after treatments. Surprisingly, systemic administration of IL‐2 for both late and early phase of HP did not recover the defect of anti‐tumor effect in the absence of CD28 signaling. Therefore, we concluded that IL‐2 production is not critical factor for the initiation of the anti‐tumor immune response induced by HP. Since our observation indicated that donor naive CD8+ T cells differentiated into TEM cells through TCM cells during HP, the mechanisms of the induction of TAA‐specific CTL in lymphopenic host is distinct from generation of effector T cells with foreign antigen and adjuvant; nevertheless CD28 is most important co‐stimulant molecule for the induction of fully functional CTLs.