Research Article: TCR stimulation strength is inversely associated with establishment of functional brain-resident memory CD8 T cells during persistent viral infection

Date Published: April 14, 2017

Publisher: Public Library of Science

Author(s): Saumya Maru, Ge Jin, Todd D. Schell, Aron E. Lukacher, Walter J. Atwood.


Establishing functional tissue-resident memory (TRM) cells at sites of infection is a newfound objective of T cell vaccine design. To directly assess the impact of antigen stimulation strength on memory CD8 T cell formation and function during a persistent viral infection, we created a library of mouse polyomavirus (MuPyV) variants with substitutions in a subdominant CD8 T cell epitope that exhibit a broad range of efficiency in stimulating TCR transgenic CD8 T cells. By altering a subdominant epitope in a nonstructural viral protein and monitoring memory differentiation of donor monoclonal CD8 T cells in immunocompetent mice, we circumvented potentially confounding changes in viral infection levels, virus-associated inflammation, size of the immunodominant virus-specific CD8 T cell response, and shifts in TCR affinity that may accompany temporal recruitment of endogenous polyclonal cells. Using this strategy, we found that antigen stimulation strength was inversely associated with the function of memory CD8 T cells during a persistent viral infection. We further show that CD8 TRM cells recruited to the brain following systemic infection with viruses expressing epitopes with suboptimal stimulation strength respond more efficiently to challenge CNS infection with virus expressing cognate antigen. These data demonstrate that the strength of antigenic stimulation during recruitment of CD8 T cells influences the functional integrity of TRM cells in a persistent viral infection.

Partial Text

Following TCR engagement, pathogen-specific naïve CD8 T cells rapidly expand to generate a large effector population to counter primary infection, with a small population of memory CD8 T cells concomitantly generated to provide accelerated immunity to re-infection. CD8 T cell activation and differentiation requires three signals: TCR stimulation (signal 1), co-stimulation (signal 2), and inflammatory cytokines (signal 3), with the duration and intensity of these signals determining whether an activated CD8 T cell is fated towards an effector or memory state [1–5]. The canonical naïve-to-effector/memory differentiation profile for CD8 T cell responses to microbial infections is derived from analyzing T cell responses in secondary lymphoid organs. Tissue-resident memory (TRM) cells apparently circumvent this differentiation schema by “locking” themselves in an effector-poised state having a transcription profile distinct from circulating central-memory and effector-memory T cells [6–10].

In this study, we show that strength of TCR stimulation is a central determinant guiding the differentiation of functional antiviral CD8 TRM cells in persistent infection. To insulate effects of TCR stimulation from dynamic changes associated with host immunity, and do so in a natural host viral infection, we mutated a weak subdominant CD8 T cell epitope in MuPyV and monitored the differentiation of donor CD8 T cells from a TCR transgenic mouse. By altering a subdominant CD8 T cell epitope within a virus and not impacting viral fitness or tropism, we circumvented variations in antigen processing, virus-associated inflammation, and host antiviral immunity that could impact T cell fate. In addition, adoptive transfer of a physiologic number of TCR transgenic CD8 T cells served to eliminate evolution of the polyclonal response and timing of T cell recruitment on T cell differentiation [39, 40]. Using this strategy, we found that infection by MuPyVs carrying altered epitopes that reduced TCR stimulation strength (1) recruited a larger number of antiviral effectors than those elicited by cognate antigen, and (2) generated a memory population in both lymphoid and nonlymphoid tissues endowed with superior recall response capability. These findings provide direct evidence that TCR signal strength, as an isolated variable, plays a dominant role in the differentiation of TRM cells.




0 0 vote
Article Rating
Notify of
Inline Feedbacks
View all comments