Can Restrain Terminal Differentiation of CD8 T Cells and Decreased T-bet Expression Increased Numbers of Preexisting Memory

Memory CD8 T cells acquire effector memory cell properties after reinfection and may reach terminally differentiated, senescent states (" Hayflick limit ") after multiple infections. The signals controlling this process are not well understood, but we found that the degree of secondary effector and memory CD8 T cell differentiation was intimately linked to the amount of T-bet expressed upon reactivation and preexisting memory CD8 T cell number (i.e., primary memory CD8 T cell precursor frequency) present during secondary infection. Compared with naive cells, memory CD8 T cells were predisposed toward terminal effector (TE) cell differentiation because they could immediately respond to IL-12 and induce T-bet, even in the absence of Ag. TE cell formation after secondary (2˚) or tertiary infections was dependent on increased T-bet expression because T-bet +/2 cells were resistant to these phenotypic changes. Larger numbers of preexisting memory CD8 T cells limited the duration of 2˚infection and the amount of IL-12 produced, and consequently, this reduced T-bet expression and the proportion of 2˚TE CD8 T cells that formed. Together, these data show that over repeated infections, memory CD8 T cell quality and proliferative fitness is not strictly determined by the number of serial encounters with Ag or cell divisions, but is a function of the CD8 T cell differentiation state, which is genetically controlled in a T-bet–dependent manner. This differentiation state can be modulated by preexisting memory CD8 T cell number and the intensity of inflammation during reinfection. These results have important implications for vaccinations involving prime-boost strategies. I t is widely accepted that having increased numbers of memory CD8 T cells correlates with better protection from secondary (2˚) infection (1–3). However, effective vaccines and immunotherapies should not only increase memory T cell numbers but also generate the most protective and pertinent types of memory cells for a given infection. CD62L hi CCR7 hi IL-7R hi CD28 hi CD27 hi central memory T cells (T CM) are commonly found in lymphoid tissues, are generally long-lived, have a high proliferative capacity, and are able to self-renew and undergo homeostatic turnover (4–9). In contrast, CD62L lo CCR7 lo CD28 lo CD27 lo effector memory T cells (T EM) appear more differentiated because they are excluded from lymphoid tissues, vary in IL-7R expression, have a reduced ability to proliferate and produce IL-2, and are more " effector-like " in the resting state (4, 6, 10–14). T EM also contain less …