Divergent molecular networks program functionally distinct CD8+ skin-resident memory T cells

Skin-resident CD8+ T cells comprise distinct IFN-γ- (TRM1) and IL-17-producing (TRM17) subsets that differentially contribute to immune responses. However, whether these populations employ common mechanisms to establish tissue residence is unknown. Here, we show that TRM1 and TRM17 cells navigate divergent trajectories to acquire tissue residency in skin. While TRM1 cells depend on a T-bet-Hobit-IL-15 axis, TRM17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in TRM17 cells parallel to that induced by Hobit in TRM1 cells, with an ICOS-c-Maf-IL-7 axis pivotal to TRM17 cell commitment. Accordingly, targeting this pathway enables ablation of skin TRM17 cells without compromising their TRM1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity., Mice
C57BL/6, B6.SJL‐PtprcaPep3b/BoyJ (CD45.1), B6.SJL‐PtprcaPep3b/BoyJ×C57BL/6 (CD45.1×CD45.2), OT-I×B6.SJL-PtprcaPep3b/BoyJ (OT-I.CD45.1), T-bet-ZsGreen×Rorgt-E2Crimson, Tgfbr2flox/flox×dLck-cre (Tgfbr2–/–), Tbx21–/–, Tbx21–/–×Eomes×Cd4cre,  Nfil3–/–, HobitTomato, Blimp1Tomato, Il15–/–, lox-stop-lox-Tgfbr1CA (Tgfbr1CA)×Cd8(E8i)cre, Tracflox/flox×Rosa26creERT2/+, Zfp683–/– (Hobit-KO), Mafflox/flox×Cd4cre (c-Maf-cKO) and Icos–/– mice were bred and maintained in the Department of Microbiology and Immunology at the The University of Melbourne, Australia. HobitTomato and Blimp1Tomato were generated by the Kallies laboratory by inserting tandem tomato expression cassettes into the endogenous Zfp683 and Blimp1 loci, respectively. For parabiosis experiments, C57BL/6 and B6.SJL‐PtprcaPep3b/BoyJ (CD45.1) mice were obtained from either the NIAID Taconic exchange program or purchased from The Jackson Laboratory and maintained at the National Institutes of Health, Bethesda, USA. Bowie×Rag1−/− tran..., , # Divergent molecular networks program functionally distinct CD8+ skin-resident memory T cells

[https://doi.org/10.5061/dryad.vq83bk40f](https://doi.org/10.5061/dryad.vq83bk40f)

This dataset contains 1) code used to compare the following cell populations and determine differential gene expression patterns and gene signatures and/or 2) associated gene expression comparison outputs (i.e. differential gene expression (DEG) lists) used to generate Figures in our manuscript listed below. For each Figure, the dataset contains code, resources or analysis outputs related to performing the following comparisons in the manners outlined in our Methodology section:

**Figure 1F and Figure 3A-F**

1. Skin Tc1 vs. Tc17 cells from Linehan *et al.* Cell 2018 (PMID 29358051)

**Figure 3A-F**
2) Trm vs. circulating T cells (i.e. generation of the Trm core signature) from Mackay *et al.* Science 2016 (PMID 27102484)
3) Hobit-KO vs. WT immune cells from Mackay *et al.* Science 2016 (PMID 27102484)
4) Bli...