Tracing TRM roots
Tissue-resident memory cells (TRM) established in peripheral tissues after initial antigen exposure are poised to rapidly respond upon reinfection. Parga-Vidal et al. used Hobit reporter/deleter mice to map the origin and differentiation of TRM cells during LCMV infection. They found that a subset of effector phase CD8+ T cells expressing the TRM-specific transcription factor Hobit selectively gave rise to TRM cells in nonlymphoid tissues and had already initiated a tissue residency transcriptional program early after infection. While the T-box transcription factor Eomes was down-regulated in Hobit+ effector cells, Eomes was found to limit TRM formation and suppress Hobit expression. These results demonstrate that TRM commitment can occur early after initial antigen exposure and provide insight into the transcription factor networks regulating TRM differentiation.
Abstract
Tissue-resident memory CD8+ T cells (TRM) constitute a noncirculating memory T cell subset that provides early protection against reinfection. However, how TRM arise from antigen-triggered T cells has remained unclear. Exploiting the TRM-restricted expression of Hobit, we used TRM reporter/deleter mice to study TRM differentiation. We found that Hobit was up-regulated in a subset of LCMV-specific CD8+ T cells located within peripheral tissues during the effector phase of the immune response. These Hobit+ effector T cells were identified as TRM precursors, given that their depletion substantially decreased TRM development but not the formation of circulating memory T cells. Adoptive transfer experiments of Hobit+ effector T cells corroborated their biased contribution to the TRM lineage. Transcriptional profiling of Hobit+ effector T cells underlined the early establishment of TRM properties including down-regulation of tissue exit receptors and up-regulation of TRM-associated molecules. We identified Eomes as a key factor instructing the early bifurcation of circulating and resident lineages. These findings establish that commitment of TRM occurs early in antigen-driven T cell differentiation and reveal the molecular mechanisms underlying this differentiation pathway.
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