Toward improved immunocompetence of adoptively transferred CD8+ T cells

Abstract

Adoptive transfer of autologous or allogenic T cells to patients is being used with increased frequency as a therapy for infectious diseases and cancer. However, many questions remain with regard to defining optimized procedures for preparation and selection of T cell populations for transfer. In a new study in this issue of the JCI, Gattinoni and colleagues used a TCR transgenic mouse model to examine in vitro-generated tumor antigen-specific CD8+ T cells at various stages of differentiation for their efficacy in adoptive immunotherapy against transplantable melanoma. The results confirm that CD8+ T cells progressively lose immunocompetence with prolonged in vitro cultivation and suggest that effector CD8+ T cells alone may be considerably less potent at protecting hosts with advanced tumors than are less differentiated T cells.

Figure 1

In vivo activation of CD8⁺ T cells is associated with downregulation of lymph node homing receptors, acquisition of effector functions, and migration to diseased tissues. When naive (N) T cells encounter antigen, they become activated and differentiate to effector (E) and memory (M) T cells. With increased antigen stimulation and T cell activation and differentiation, effector T cells progressively lose telomere length and proliferative potential, may become exhausted (E_exh) and/or senescent (E_sen), and/or may undergo apoptosis. Lymph node homing receptor CD62L and CC chemokine receptor 7 (CCR7) are downregulated when T cells differentiate to effector T cells. At the same time, effector T cells acquire the expression of IFN-γ and the cytolytic proteins perforin and granzymes. The figure represents a simplified scheme; for more comprehensive overviews see, for example, refs. –.