Search

Tissue-resident memory CD8 + T cells (T RM cells) are crucial in protecting against reinvading pathogens, but the impact of reinfection on their tissue confinement and contribution to recall responses is unclear. We developed a unique lineage tracer mouse model exploiting the T RM -defining transcription factor homolog of Blimp-1 in T cells (Hobit) to fate map the T RM progeny in secondary responses. After reinfection, a sizeable fraction of secondary memory T cells in the circulation developed downstream of T RM cells. These tissue-experienced ex-T RM cells shared phenotypic properties with the effector memory T cell population but were transcriptionally and functionally distinct from other secondary effector memory T cell cells. Adoptive transfer experiments of T RM cells corroborated their potential to form circulating effector and memory cells during recall responses. Moreover, specific ablation of primary T RM cell populations substantially impaired the secondary T cell response, both locally and systemically. Thus, T RM cells retain developmental plasticity and shape both local and systemic T cell responses on reinfection.

Tissue-resident memory CD8 + T (T RM ) cells that develop in the epithelia at portals of pathogen entry are important for improved protection against re-infection. CD8 + T RM cells within the skin and the small intestine are long-lived and maintained independently of circulating memory CD8 + T cells. In contrast to CD8 + T RM cells at these sites, CD8 + T RM cells that arise after influenza virus infection within the lungs display high turnover and require constant recruitment from the circulating memory pool for long-term persistence. The distinct characteristics of CD8 + T RM cell maintenance within the lungs may suggest a unique program of transcriptional regulation of influenza-specific CD8 + T RM cells. We have previously demonstrated that the transcription factors Hobit and Blimp-1 are essential for the formation of CD8 + T RM cells across several tissues, including skin, liver, kidneys, and the small intestine. Here, we addressed the roles of Hobit and Blimp-1 in CD8 + T RM cell differentiation in the lungs after influenza infection using mice deficient for these transcription factors. Hobit was not required for the formation of influenza-specific CD8 + T RM cells in the lungs. In contrast, Blimp-1 was essential for the differentiation of lung CD8 + T RM cells and inhibited the differentiation of central memory CD8 + T (T CM ) cells. We conclude that Blimp-1 rather than Hobit mediates the formation of CD8 + T RM cells in the lungs, potentially through control of the lineage choice between T CM and T RM cells during the differentiation of influenza-specific CD8 + T cells.

CD8 T cells acquire cytotoxic molecules including granzyme B during effector differentiation. Both tissue-resident memory CD8 T cells (Trm) and circulating CD45RA + effector-type T cells (Temra) cells have the ability to retain granzyme B protein expression into the memory phase, but it is unclear how this persistence of cytolytic activity is regulated during steady state. Previously, we have described that the transcriptional regulators Hobit and Blimp-1 have overlapping target genes that include granzyme B, but their impact on the regulation of cytotoxicity in Trm and Temra cells during homeostasis has remained unclear. We examined the expression regulation of Hobit and Blimp-1 in murine and human CD8 T-cells to determine their timeframe of activity. While Blimp-1 mRNA was expressed throughout effector and memory T cells, Blimp-1 protein, was only transiently expressed during the effector stage. In contrast, Hobit mRNA and protein expression was stably maintained during quiescence, but downregulated after activation. Notably, Blimp-1 was required for expression of granzyme B in murine effector T cells and Trm, while Hobit specifically regulated granzyme B in murine Trm during the memory phase. These findings suggest that Blimp-1 initiates cytotoxic effector function and that Hobit maintains cytotoxicity in a deployment-ready modus in Trm., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)