Targeting tissue-resident memory CD8+ T cells in the kidney is a potential therapeutic strategy to ameliorate podocyte injury and glomerulosclerosis.

Although tissue-resident-memory T (TRM) cells, a recently identified non-circulating memory T cell population, play a crucial role in mediating local immune responses and protect against pathogens upon local reinfection, the composition, effector function, and specificity of TRM cells in the kidney and their relevance for chronic kidney disease remain unknown. In this study, we found that renal tissue displayed high abundance of tissue-resident lymphocytes, and the proportion of CD8+ TRM cells was significantly increased in the kidney from patients and mice with focal segmental glomerulosclerosis (FSGS), diabetic kidney disease (DKD), and lupus nephritis (LN). Mechanistically, IL-15 significantly promoted CD8+ TRM cell formation and activation, thereby promoting podocyte injury and glomerulosclerosis. Interestingly, Sparsentan, the dual angiotensin II (Ang II) receptor and endothelin type A receptor antagonist, can also reduce TRM cell responses by intervening IL-15 signaling, exploring its new pharmacological functions. Mechanistically, Sparsentan inhibited Ang II or endothelin-1 (ET-1)-mediated IL-15 signaling, thereby further regulating renal CD8+ TRM cell fates. Collectively, our studies provide direct evidence for the pivotal role of renal CD8+ TRM cells in podocyte injury and further strengthen that targeting TRM cells represents a novel therapeutic strategy for patients with glomerular diseases.

Novel insights into contact dermatitis.

Contact dermatitis is a common disease that is caused by repeated skin contact with contact allergens or irritants, resulting in allergic contact dermatitis (ACD) and/or irritant contact dermatitis. Attempts have been made to identify biomarkers to distinguish irritant and allergic patch test reactions, which could aid diagnosis. Some promising candidates have recently been identified, but verification and validation in clinical cases still need to be done. New causes of ACD are constantly being recognized. In this review, 10 new contact allergens from recent years, several relating to anti-aging products, have been identified. Frequent allergens causing considerable morbidity in the population, such as the preservative methylisothiazolinone, have been regulated in the European Union. A significant drop in the number of cases has been seen, whereas high rates are still occurring in other areas such as North America. Other frequent causes are fragrance allergens, especially the widely used terpenes and acrylates found in medical devices for control of diabetes. These represent unsolved problems. Recent advances in immunology have opened the way for a better understanding of the complexity of contact dermatitis, especially ACD-a disease that may be more heterogenous that previous understood, with several subtypes. With the rapidly evolving molecular understanding of ACD, the potential for development of new drugs for personalized treatment of contact dermatitis is considerable.

Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis.

BACKGROUND: Natural killer T (NKT) cells are unconventional T cells that bridge innate and adaptive immunity. NKT cells have been implicated in the development of atopic dermatitis (AD). OBJECTIVE: We aimed to investigate the role of NKT cells in AD development, especially in skin. METHODS: Global proteomic and transcriptomic analyses were performed by using skin and blood from human healthy-controls and patients with AD. Levels of CXCR4 and CXCL12 expression in skin NKT cells were analyzed in human AD and mouse AD models. By using parabiosis and intravital imaging, the role of skin CXCR4+ NKT cells was further evaluated in models of mice with AD by using CXCR4-conditionally deficient or CXCL12 transgenic mice. RESULTS: CXCR4 and its cognate ligand CXCL12 were significantly upregulated in the skin of humans with AD by global transcriptomic and proteomic analyses. CXCR4+ NKT cells were enriched in AD skin, and their levels were consistently elevated in our models of mice with AD. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Similar to tissue-resident memory T cells, the predominant skin NKT cells were CXCR4+ and CD69+. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in the liver, spleen, and lymph nodes. Skin fibroblasts were the main source of CXCL12. CXCR4+ NKT cells preferentially trafficked to CXCL12-rich areas, forming an enriched CXCR4+ tissue-resident NKT cells/CXCL12+ cell cluster that developed in acute and chronic allergic inflammation in our models of mice with AD. CONCLUSIONS: CXCR4+ tissue-resident NKT cells may form a niche that contributes to AD, in which CXCL12 is highly expressed.

Tissue-resident memory CD8+ T cells in cancer immunology and immunotherapy.

Memory T cells can be generated and remain long-term in different tissues following infection or immunization. Tissue-resident memory T (TRM) cells are a unique group of memory T cells that form and persist mainly in peripheral non-lymphoid organs. Unlike effector or central memory T (TEM or TCM) cells, TRM cells do not circulate to the blood but can provide a rapid and robust local response to re-infection. Recently, a large body of clinical studies has shown that CD103+ CD8+ TRM-like cells also exist intratumorally and strongly correlate with favorable prognosis in cancer patients. Cancer vaccine-induced CD103+ CD8+ TRM cells have been reported to suppress tumor growth in mouse models. This suggests that CD8+ TRM-like cells play a crucial role in cancer immunosurveillance and immunotherapy. In this review, we focus on the features and cytotoxic mechanisms of CD8+ TRM-like cells in multiple solid tumors and discuss their potential implications for cancer immunotherapy. We believe a better understanding of the generation, function, and longevity of CD8+ TRM-like cells in the tumor microenvironment will provide new insights for cancer immunotherapies.

Metabolic regulation of tissue-resident memory CD8+ T cells.

Intracellular metabolic adaptations help define the function and homeostasis of memory CD8+ T cells. These cells, which promote protection against infections or cancer, undergo consecutive metabolic shifts, ultimately relying on mitochondrial-related pathways. Past CD8+ T cell metabolism studies focused on circulating memory cells, which are exclusive to secondary lymphoid organs or recirculate between lymphoid and non-lymphoid organs. Yet, now there is unequivocal evidence that memory CD8+ T cells reside in many non-lymphoid organs and mediate protective immunity in barrier tissues. The metabolic adaptations occurring in forming and established tissue-resident memory CD8+ T cells are currently subject of intense research. In this review, we discuss the latest breakthroughs on the transcriptional and protein control of tissue-resident memory CD8+ T cell metabolism.

Pathogenic role of tissue-resident memory T cells in autoimmune diseases.

The tissue-resident memory T (TRM) cells constitute a newly identified subset of memory T cells which are non-circulating and they persist for long-term in epithelial barrier tissues, including skin, lung, gastrointestinal tract and reproductive tract, and in non-barrier tissues, including brain, kidney, pancreas and joint. These cells provide rapid on-site immune protection against previous exposed pathogens in peripheral tissues. There cells are transcriptionally, functionally and phenotypically distinguished from circulating effector memory T cells. In addition to their protective functions, increasing evidence reveals that autoreactive and/or aberrantly activated TRM cells may be involved in the pathogenesis of autoimmune disorders such as psoriasis and, as recently reported, may contribute to vitiligo, autoimmune hepatitis and rheumatoid arthritis. Therefore, this review aims to summarize the current progress in the biology of TRM cells, such as the newly identified TRM markers, upstream regulators, and the functions of TRM cells. We also discuss the contributions of TRM cells to the development of autoimmunity to broaden our understanding of autoimmune diseases and to provide novel potential therapeutic strategies for these diseases.