The gastrointestinal tract is a site of high immune challenge, as it must maintain a delicate balance between tolerating luminal contents and generating an immune response toward pathogens. CD4+ T cells are key in mediating the host protective and homeostatic responses. Yet, CD4+ T cells are also known to be the main drivers of inflammatory bowel disease (IBD) when this balance is perturbed. Many subsets of CD4+ T cells have been identified as players in perpetuating chronic intestinal inflammation. Over the last few decades, understanding of how each subset of Th cells plays a role has dramatically increased. Simultaneously, this has allowed development of therapeutic innovation targeting specific molecules rather than broad immunosuppressive agents. Here, we review the emerging evidence of how each subset functions in promoting and sustaining the chronic inflammation that characterizes IBD.

Intestinal GrA + Th cells in aGVHD represent a distinct Th lineage. Although the cellular sources were not defined, enhanced Gzma expression was previously observed in the intestines during aGVHD but only minimally in the skin and lymphoid organs (11). At 10 days post-HCT, we observed significantly increased expression of Gzma in both the small intestine (SI) and large intestine (LI) of mice that received allogeneic bone marrow and T cells as compared with syngeneic controls (P = 0.01 and P < 0.0001, respectively, Figure 1A). We observed a population of GrA + CD8 + T cells in all organs examined in allogeneic recipients that was present in lower percentages in syngeneic recipients (Figure 1, B and C). Unexpectedly, CD4 + T cells also produced GrA in allogeneic recipients and were the dominant population of GrA-producing T cells within the small and large intestines, the latter being where CD4 + T cells accounted for approximately 75% of the GrA-producing cells (Figure 1, B-D). A limited proportion of intestinal GrA + Th cells coexpressed GrB in the SI or LI, indicating that these cells did not acquire a classic cytotoxic phenotype (Figure 1E) (12-15). GrA + cells did not coexpress FOXP3 or IL-17A (Figure 1E) but exhibited partial coexpression of IFN-γ, which was slightly more pronounced in the LI versus the SI (~40% vs. ~30%, Figure 1E). To determine if GrA + Th cells were related to IFN-γ-producing Th1 cells, we analyzed lineage-specific cytokine and transcription factor expression (Supplemental Table 2; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.124465DS1) within intestinal CD3 + CD4 + T cells using time-of-flight cytometry (CyTOF). GrA + Th cells were spatially clustered, indicating that GrA expression is limited to a distinct population of Th cells and is not shared by multiple Th subsets (Figure 1F). In contrast, IFN-γ + Th cells were distributed between 2 major populations, those that spatially segregated with TNF + IL-2 + cells (i.e., prototypic Th1 cells) and those that partially overlapped with GrA + Th cells (Figure 1F). Cells that expressed high levels of GrA exhibited minimal overlap with other lineage-specific cytokines, many of which were expressed in low amounts (Supplemental Figure 1). These data indicate that GrA + Th cells are not typical Th1 cells and may represent a novel Th cell type that responds to signals involved with intestinal damage or inflammation. GrA is expressed by human Th cells in a PBMC-induced model of GVHD. Our data indicate that CD4 + Th cells are an important source of GrA and thus may be relevant to human GVHD. To examine this further, we adopted an established model (16) of human PBMC-induced GVHD in immune-compromised NRG mice. Briefly, human PBMCs from 2 individual donors were injected into NRG mice, and mice were monitored until they reached 20% body weight loss or a significant clinical score (>3). At this endpoint, mice were euthanized, and immune cells were isolated from the spleen, liver, SI, and LI and analyzed fo...

Langerhans cells (LC) are the prototype langerin-expressing dendritic cells (DC) that reside specifically in the epidermis, but langerin-expressing conventional DCs also reside in the dermis and other tissues, yet the factors that regulate their development are unclear. Because retinoic acid receptor alpha (RARα) is highly expressed by LCs, we investigate the functions of RARα and retinoic acid (RA) in regulating the langerin-expressing DCs. Here we show that the development of LCs from embryonic and bone marrow-derived progenitors and langerin+ conventional DCs is profoundly regulated by the RARα-RA axis. During LC differentiation, RARα is required for the expression of a LC-promoting transcription factor Runx3, but suppresses that of LC-inhibiting C/EBPβ. RARα promotes the development of LCs and langerin+ conventional DCs only in hypo-RA conditions, a function effectively suppressed at systemic RA levels. Our findings identify positive and negative regulatory mechanisms to tightly regulate the development of the specialized DC populations.

CD4 T cells play important roles in promoting protective immunity and autoimmune disease. A great deal of attention has been given to the differentiation and function of subsets of cytokine-producing CD4 T cells (i.e., Th1, Th2, and Th17 cells) in these settings. However, others have also observed the accumulation of granzyme-producing CD4 T cells in tumors and in autoimmune patients that are distinct from their cytokine-producing counterparts. Despite the relatively large numbers of granzyme-producing cells in diseased tissues, their roles in driving disease have remained enigmatic. This review will focus on the phenotype(s) and roles of granzymeproducing CD4 T cells in cancer and autoimmunity. We will also examine how granzyme-producing cells interact with current therapeutics and speculate how they may be targeted during disease. ImmunoHorizons, 2021, 5: 909-917.

The synergistic effect in multi‐metal electrocatalysts has gained attention as an efficient strategy for enhancing intrinsic electrocatalytic activities. In this study, a facile electrodeposition technique is used to synthesize a multi‐metal high entropy catalyst (HEC) for efficient electrocatalytic hydrogen production. To boost the synergistic effect between noble metals and transition metals, the Pt ratio is controlled in a multi‐metal electrocatalyst system. The prepared Pt‐involved HEC (Pt‐HEC) exhibits a bamboo‐like morphology with uniformly distributed elements. The 2.5 mM Pt‐HEC has outstanding electrocatalytic activity toward hydrogen evolution reaction (HER) among other Pt‐HECs, with a low overpotential of 70 mV and a Tafel slope value of 47 mV dec−1. Additionally, the Pt mass activity of the 2.5 mM Pt‐HEC is 5.6 times higher than commercial Pt/C electrocatalyst owing to the improved synergistic effect with an optimized Pt ratio. According to the electrochemical impedance spectroscopy (EIS) analysis, the proton‐coupled electron transfer (PCET) process occurs more quickly in the 2.5 mM Pt‐HEC electrocatalyst, confirming its smaller charge transfer resistance properties compared to those of the 5 and 1 mM Pt‐HEC. Therefore, HEC systems can be extensively encouraged as a platform for improving synergistic effects and enhancing electrocatalytic activities for a highly efficient HER electrocatalyst.