CD8+ T Cell Activation Leads to Constitutive Formation of Liver Tissue-Resident Memory T Cells that Seed a Large and Flexible Niche in the Liver

Abstract

Graphical Abstract Highlights d TCR stimulation is essential for liver Trm cell formation d Liver Trm cells require IL-15 d Local antigen presentation and inflammation enhance liver Trm cell formation d Newly formed liver Trm cells do not displace existing Trm cell populations SUMMARY Liver tissue-resident memory T (Trm) cells migrate throughout the sinusoids and are capable of protecting against malaria sporozoite challenge. To gain an understanding of liver Trm cell development, we examined various conditions for their formation.Although liver Trm cells were found in naive mice, their presence was dictated by antigen specificity and required IL-15. Liver Trm cells also formed after adoptive transfer of in vitro-activated but not naive CD8 + T cells, indicating that activation was essential but that antigen presentation within the liver was not obligatory. These Trm cells patrolled the liver sinusoids with a half-life of 36 days and occupied a large niche that could be added to sequentially without effect on subsequent Trm cell cohorts. Together, our findings indicate that liver Trm cells form as a normal consequence of CD8 + T cell activation during essentially any infection but that inflammatory and antigenic signals preferentially tailor their development.

The Whole Body as the System in Systems Immunology

“…In lymphoid sites, such as lymph nodes, tissue memory T cells exhibit increased expression of transcription factors and functional markers associated with stemness and denoting maintenance in a more quiescent state compared with memory T cells in spleen and bone marrow, which exhibit a more differentiated state with increased turnover ( Miron et al., 2018 ). Conversely, T RM localized across the GI tract exhibit distinct phenotypes and metabolic signatures whether they localize to the small intestine, associated lymphoid tissue, or the pancreas ( Weisberg et al., 2019 ), and unique localization of T RM in liver sinusoids requires specific adaptations ( Holz et al., 2018 ; McNamara et al., 2017 ). Further elucidation of tissue memory T cell heterogeneity and tissue adaptations will be facilitated by applying scRNA-seq technologies.…”

Single-Dose Vaccination with a Hepatotropic Adeno-associated Virus Efficiently Localizes T Cell Immunity in the Liver with the Potential To Confer Rapid Protection against Hepatitis C Virus

“…Several studies have shown that local antigen encounter or deposition usually perpetuates the establishment of high numbers of CD8 ϩ T RM cells in various anatomical sites, including the liver (12,(52)(53)(54). Studies in mice and humans suggest that i.v.…”

“…DNA immunization occurs in the draining cervical lymph nodes (28,35) and likely does not facilitate local antigen encounter/deposition in the liver to establish high numbers of intrahepatic CD8 ϩ T RM cells. A caveat with this interpretation is that a recent study that analyzed adoptively transferred CD8 ϩ T cells showed that the lodgment of CD8 ϩ T RM cells in the liver is both activation and interleukin-15 (IL-15) dependent, and inflammatory signals (e.g., type I interferon inducers) can enhance the number of intrahepatic CD8 ϩ T RM cells (54). Thus, in addition to facilitating local antigen encounter, rAAV-NS5B vaccination could induce higher levels of IL-15 and relevant inflammatory signals compared to pVAX-NS5B-PRF vaccination in order to increase the numbers of intrahepatic CD8 ϩ T RM cells.…”

“…Collectively, these studies suggest that a stable and durable population of NS5Bspecific CD8 ϩ T RM cells has formed following rAAV-NS5B vaccination. A caveat is that a recent study showed that T RM cells that form in the liver in recipient mice adoptively transferred with in vitro-activated OT-I CD8 ϩ T cells or PbT-I cells that are later primed with radiation-attenuated sporozoite (RAS) vaccination have a half-life of 36 or 28 days, respectively (54). Thus, future studies could also determine the half-life of the intrahepatic CD8 ϩ T RM cells that form following rAAV vaccination, which will be important for understanding the limitations and strengths of using rAAV to elicit a stable population of intrahepatic CD8 ϩ T RM cells.…”

A new era of rational malaria vaccine development

“…To put this into perspective, liver T RM cells induced by an RAS vaccine in a similar model only had an estimated halflife of 28 days and with multiple dosing required to achieve a significant level of protection. 5,10 The new vaccine candidate developed by Holz et al represents an important advance in global efforts toward developing a malaria vaccine. However, some caveats will need to be addressed, including several translational challenges.…”