Continuous Effector CD8 + T Cell Production in a Controlled Persistent Infection Is Sustained by a Proliferative Intermediate Population

Abstract

Summary Highly functional CD8+ effector T (Teff) cells can persist in large numbers during controlled persistent infections, as exemplified by rare HIV-infected individuals who control the virus. Here we examined the cellular mechanisms that maintain ongoing T effector responses using a mouse model for persistent Toxoplasma gondii infection. In mice expressing the protective MHC-I molecule, Ld, a dominant T effector response against a single parasite antigen was maintained without a contraction phase, correlating with ongoing presentation of the dominant antigen. Large numbers of short-lived Teff cells were continuously produced via a proliferative, antigen-dependent intermediate (Tint) population with a memory-effector hybrid phenotype. During an acute, resolved infection, decreasing antigen load correlated with a sharp drop in the Tint cell population, and subsequent loss of the ongoing effector response. Vaccination approaches aimed at the development of Tint populations may prove effective against pathogens that lead to chronic infection.

CD8 + T Lymphocyte Self-Renewal during Effector Cell Determination

“…In the setting of controlled persistent infection, a proliferative intermediate population appears to enable the continuous production of effector cells (Chu et al, 2016). In chronic active infections, a similar self-renewal property has been identified among a TCF1 hi subpopulation of cells, although the natural history of those diseases appears to outstrip the normal limits of T cell regenerative capacity (He et al, 2016; Im et al, 2016; Leong et al, 2016; Utzschneider et al, 2016).…”

“…Despite their rapid division and heightened state of activation and differentiation, we now show that the initial effector-prone daughter cells actually retain the key memory-like property of progenitor cell self-renewal while producing their determined effector cell progeny. Production of the opposing outcomes of differentiation and self-renewal by effector-prone progenitors may explain why memory cells could have appeared to be derived from effector cells (Restifo and Gattinoni, 2013) and may provide a unifying framework for classifying antigen-activated T cell fates during successful and unsuccessful settings of long-term clonal T cell regeneration (Chu et al, 2016; He et al, 2016; Im et al, 2016; Leong et al, 2016; Utzschneider et al, 2016). …”

CD103+ CD8 T Cells in the Toxoplasma-Infected Brain Exhibit a Tissue-Resident Memory Transcriptional Profile

“…Support for the unique heterogeneity and complexity of the T cell population during chronic T. gondii infection is provided by the recent characterization of the T INT population (9). Such cells serve as a pool from which to quickly generate effector T cells during persistent infection and serve as additional evidence that chronic infection produces unique T cell phenotypes compared to acute infections.…”

“…Although protection could be mediated in part by a continuous pool of effector cells, there is also evidence of the involvement of memory T cell subsets (1, 7–9). Mice chronically infected with T. gondii exhibit protection against challenge with the virulent RH strain of the parasite, which is lethal in naïve mice (10).…”

“…During chronic infection, memory T cells require unique survival signals (14) and can acquire distinct phenotypes, including an exhausted/attenuated phenotype (15). In chronic T. gondii infection, the recent discovery of a T cell population in an intermediate state (T INT ) between memory and effector status provides an important clue to understanding the coordination of the T cell response in this context (9). Nevertheless, during chronic infection, the unique role for a memory response as opposed to the effector response remains undefined.…”