Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• CD8+ resident memory T cells

• Lymph node T cell trafficking

• Murine skin infection model

• Dermal lymphatic vessels

Main Findings

Tissue-resident memory T cells (TRM) are important effectors of the local immune system in and provide rapid protection in peripheral tissue to pathogens and cancer. Historically, their tissue residency is defined by their lack of recirculation and potential to initiate an immediate memory response in barrier tissues. Specifically in the skin, which is constantly exposed to multiple environmental triggers, the presence of TRM is crucial to host immunity. Skin TRM are defined by the high expression of CD69 and CD103 and a downregulation of CD62L (CD69+, CD103+, CD62L-) which are thought to tether these cells in the tissue to prevent them from egressing. Over recent years, TRM have also been described in the lymph nodes (LN) using different infection models. However, whether these cells are true bona-fide TRM or if they are just non-lymphoid tissue TRM that have migrated to the LN, has not been established thus far.

The data presented in Heim et. al. adds to the emerging paradigm that CD8+ skin TRM could be primed in the skin and can egress from infected skin into the draining lymph node (dLN) where they establish a LN residency phenotype to provide local protection in peripheral tissue. Using a localized infection model of vaccinia virus scarification of the ear skin combined with different genetic models, the authors show that lymph node TRM are only present in the dLN, but not in distal LN or spleen and appear concurrently with skin TRM. Moreover, they demonstrate that, while TRM development in the skin was independent of lymphatic vessels, trafficking of skin effector T cells to the dLN is necessary for LN TRM development, initiating a residency program in these cells. Lastly, the authors show that the antigen recognition of LN TRM happens in the skin and LN TRM have increased potential to rapidly act to control subsequent viral challenge by reducing LCMV load in the dLN. Overall, the retrograde migration of virus-specific T cells from the skin to the dLN is shown in a convincing manner and provides additional evidence to show that TRM have potential to migrate and highlights that antigen encounter in the tissue is central to the establishment of LN TRM.

Limitations

• Mechanistic insight into the observed retrograde migration from skin to lymph node would add even more to this paper. Ideally, the authors could specify the specific receptors are up/downregulated to enable specific migration to the dLN after skin infection. Even better, it would be ideal if the authors could shed light on how the CD8 T cells enter the skin or whether the cells have been already locally present.

• While scRNA-seq data of Kaede mice is an interesting experimental setup to show T cell origin and migration, this data could have been explored more for novel markers of skin-derived LN TRM instead of just highlighting known TRM markers.

• While this manuscript shows the migration of effector T cell to LN convincingly, it would have been to use their re-challenge model from Fig. 6 to investigate whether LN TRM can migrate back to the skin to assert an effector function. This could also be shown by re-challenging the same ear with vaccinia virus and track LN TRM back to the skin.

• Given that antigen recognition by T cells in the non-lymphoid tissue appears to enhance TRM formation, it was unclear whether the antigen presentation occurs in the infected skin or in the dLN. Perhaps screening for receptors that are involved in CD4+ T cell egress may provide insight into when/where the antigen recognition occurs.

• An additional important point, that the study (understandably) doesn’t delve into much detail, is whether this type of migration and TRM seeding in the LN is specific to the skin or also exists in other barrier sites. It would be intriguing to analyse whether intestinal infections would result in similar TRM behaviours, using mesenteric LNs as dLN.

• The ending with Fig. 6 seems a bit abrupt and an additional functional readout (e.g. ex vivo killing assay) would have added to the claim that LN TRM have increased cytotoxic potential.

Significance/Novelty

This preprint uses a well-defined spatially-restricted mouse model of skin infection to elegantly show how T cell trafficking from tissue via the dermal lymphatics is central to the establishment of a resident CD8+ T cell population in peripheral tissue. Further, showing that virus-specific effector T cells egressing out of the skin are the precursors to LN TRM provides better insight into the development of these cells and answers the question of whether or not LN TRM are directly related to a non-lymphoid tissue of origin.

Credit

Reviewed by Teresa Neuwirth and Azuah Gonzalez as part of a cross-institutional journal club between the Vanderbilt University Medical Center (VUMC), the Max-Delbrück Center Berlin, the Medical University of Vienna and other life science institutes in Vienna.

The author declares no conflict of interests in relation to their involvement in the review.