Paper Reading
01
T Helper Cell Cytokines Modulate Intestinal Stem Cell Renewal and Differentiation
Cell
To search for an ISC-immune cell interaction, authors queried their recent scRNA-seq data of 1,522 EpCAM+intestinal epithelial cells (IECs) from wild-type (WT) and Lgr5- GFP mice forgenes expressed by ISCs that encode cell surface or secreted proteins known to interact with immune cells. By expression signatures, flow cytometry, and immunofluorescence assays, they identified an ISC subset that is low-cycling(ISC-I), and two more proliferative ISC subsets (ISC-II and -III). Pseudotimeanalysis suggested that ISC-I have the most stem-like features, while ISC-II and ISC-III are progressively more differentiated. Querying annotated receptor genes that are differentially expressed between ISCs and the other IEC sidentified Cd74, which encodes the invariant chain of the MHCII complex, as enriched in ISCs. They showed that MHCII+ Lgr5+ ISCs (ISC-II and -III) are more proliferative then ISC-I.
Researchers futher hypothesized that among IECs, it is Lgr5+ ISCs that interact with Th cells via MHCII, they sorted EpCAM+ cells, which contain Lgr5+ ISCs and cultured them with DQovalbumin. Compared to EpCAM+ GFP cells, co-culture with Lgr5-GFP+ ISCs or DCs caused substantially higher OTII activation by IL-2 secretion. They showed that Lgr5+ ISCs activate Th cells in vitro in an antigen-specific manner.
Next, they analyzed scRNAseq data of 9,842 IECs and 5,122 CD45+ immune cells from mice infected with Salmonella entericaor Heligmosomoides polygyrus to examine IEC remodeling in vivo. There was amild reduction in the expression of a panstem signature, but a substantial increase in MHCII expression and a shift in the relative proportions of the three ISC subsets, with reduction in cells expressing the ISC-I program and elevation of those expressing the ISC-II and -III programs. Compared to a-IgG treated control, mice treated with a-MHCII showed reduced tuft cell proportions post-infection and increased ISC proportions. They therefore tested the impact of MHCII deletion in IECs during H. polygyrus infection, using either a constitutive epithelial H2-Ab1 KO driven by the Villin promoter. Lgr5 expression was upregulated in MHCIIDISC mice during infection compared toMHCIIfl/fl controls. Importantly, MHCIIgut-/- mice had higher worm burden compared to MHCIIfl/fl controls after 6 weeks of infection.
They performed scRNA-Seq of CD45+ cells from the LP of MHCII gut-/- and MHCIIfl/fl mice, at homeostasis and 4 days post-infection, and tested immune cell markers in situ. The results suggest that MHCII expression by epithelial cells impacts both the innate and adaptiveresponses, some of which may propagate in direct effects, for example dendriticcells during infection. To examine the role of T cells in Lgr5+ ISC differentiation axis, they next assessed two T cell-deficient mouse models.Tcell (or only a/b T cells) ablation leads to ISCs accumulation, possibly due to diminished differentiation capacity, in particular toward the absorptive lineage.
In the end, in their organoid assays, only Treg cells and their key cytokine IL10 promoted renewal of the ISC pool. They used Foxp3-DTR mice confirm this in vivo. The reduction in ISCs and a shift toward more MHCII+proliferative ISCs in Foxp3-DTR mice supports a model of higher differentiation rates and stem cell pool depletion.
02
PD-1 and LAG-3 dominate checkpointreceptor-mediated T cell inhibition in renal cell carcinoma
Cancer Immunol Res
Firstly，Authors checked the expression of five common iR, i.e. PD-1, LAG-3, Tim-3, BTLA and CTLA-4which was assessed on CD8+ and on non-Treg CD4+ cells (CD4+ Tconv) in TILs andautologous PBMCs. Among of them, PD-1 and LAG-3 were the most frequently upregulated iR within RCC TILs. As a comparison, iR expression was also evaluated on CD8+ T cells and CD4+ Tconv in PBMCs from healthy blood bankdonors (HD_PBMCs)
Then they found that the median frequencies of PD-1+ , LAG-3+ , Tim-3+ and CTLA-4+ (only on CD4+ Tconv) T cells were significantly increased in TILs compared to autologous blood T cells; inparticular, PD-1 was increased by at least 2-fold in TILs versus PBMCs in morethan 69% of the patients. Interestingly, the expression of LAG-3 on CD8+ Tcells appeared to define two groups of patients with moderate.The two main subgroups of patients (groups 1 and 2), whereby group 1 was dominantly characterized by no expression of LAG-3 and group 2 by coordinated and frequent expression of LAG-3: when LAG-3 expression was prominent, they could mostlydetect high frequencies of LAG-3+ cells in all cell compartments.Patients from group 2 showed significantly higher LDH serum concentrations compared topatients from group 1. Baseline levels of LDH are associated with survival upon checkpoint blockade therapy
Altogether, researchers found that majority(between 50% and 65%) of the CD4+ and CD8+ potential TIL effectors did express either PD-1 and/or LAG-3, often together with Tim-3, whereas approx. one fourth did not express any of the 5 iR tested. the most frequent iR combination was PD-1 and LAG-3 without BTLA, CTLA-4 and Tim-3. Finally, when considering PD-1+cells, which was the most frequent subpopulation in single iR analysis, LAG-3was co-expressed in approximately half of the cells.
They calculated the mean fold change derived from all three functional parameters for each experiment and compared this mean fold change for single PD-1 blockade to blockade of PL or PT . WhenLAG-3 was additionally blocked, immune function was improved in 12 of 19 patients (63%). For Tim-3 co-blockade, this enhancement was seen in only one of seven patients (14%), indicating that dual PD-1 + LAG-3, but not PD-1 + Tim-3 blockade, is improving immune functions of stimulated RCC TILs. Finally, they found the expression of the receptors PD-1, LAG-3 and Tim-3 was assessedindividually in a subgroup of patient samples after the 3-day culture. Based onfunctional experiments, they propose that clinical targeting of PD-1 togetherwith LAG-3 might show synergistic effects and increase clinical response ratesin RCC patients.
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