Defective Central Memory CD8⁺ T Cell Differentiation in the Absence of Eomesodermin.

Abstract 2662

Poster Board II-638

The differentiation of central memory CD8⁺ T cells after vaccination or primary pathogen encounter is critical for the establishment of long-lasting protection against pathogens including intracellular infectious organisms and malignancies. Unfortunately, the mechanisms of immune memory establishment are unclear, preventing the development of effective vaccines to many emerging pathogens. Naïve CD8⁺ T cells responding to intracellular pathogens undergo rounds of cell division and progressive differentiation to give rise to terminally differentiated effector cells and memory cells to provide acute and long-lasting immunity, respectively. T-bet and Eomesodermin (Eomes), key transcription factors in this differentiation, share significant DNA binding domain sequence and functional homology, although their distinct expression patterns and non-DNA binding domains suggest potential non-redundant functions. T-bet drives effector and effector-memory differentiation, suppressing the formation of long-lasting central memory CD8⁺ T cells. We now show that CD8⁺ T cells responding to acute infection with the lymphocytic choriomeningitis virus (LCMV) display significant heterogeneity in the relative expression levels of T-bet and Eomes on a single cell level. Using mice with a tissue specific deletion of Eomes in T cells, we show defective central-memory differentiation in CD8⁺ T cells lacking Eomes after infection with LCMV. We observe defects in both long-term persistence and re-expansion on re-challenge, two defining characteristics of central-memory T cells, in memory CD8⁺ T cells lacking Eomes. These results demonstrate that, in direct contrast to T-bet, Eomes promotes central-memory CD8⁺ T cell differentiation. Thus, the balance of T-bet and Eomes expression may determine the propensity for CD8⁺ T cell terminal effector differentation versus long-lived memory differentiation. Our findings demonstrate a crucial role for Eomes in the differentiation of pathogen specific central memory CD8⁺ T cells which can provide life-long immune protection.