Naive, effector, and memory CD8 T cells in protection against pulmonary influenza virus infection: Homing properties rather than initial frequencies are crucial

The goal of adoptive immunotherapy is to target a high number of persisting effector cells to the site of a virus infection or tumor. In this study, w e compared the protective value of hemagglutinin peptide-specific CD8 T cel ls generated from the clone-4 TCR-transgenic mice, defined by different sta ges of their differentiation, against lethal pulmonary influenza infection. We show that the adoptive transfer of high numbers of Ag-specific unprimed , naive CD8 T cells failed to clear the pulmonary virus titer and to promot e host survival, The same numbers of in vitro generated primary Ag-specific Tc1 effector cells, producing high amounts of IFN-gamma, or resting Tc1 me mory cells, generated from these effecters, were protective. Highly activat ed CD62L(low) Tc1 effecters accumulated in the lung with rapid kinetics and most efficiently reduced the pulmonary viral titer early during infection. The resting CD62L(high) naive and memory populations first increased in ce ll numbers in the draining lymph nodes. Subsequently, memory cells accumula ted more rapidly and to a greater extent in the lung lavage as compared wit h naive cells, Thus, effector cells are most effective against a localized virus infection, which correlates with their ability to rapidly distribute at the infected tissue site. The finding that similar numbers of naive Ag-s pecific CD8 T cells are not protective supports the view that qualitative d ifferences between the two resting populations, the naive and the memory po pulation, may play a major role in their protective value against disease.