Biology subjects

Constantinides, M. G.

Publications and source records attributed to Constantinides, M. G..

4 recordsLinked to original sources

bioRxiv2026

Mucosal-associated invariant T cells support IL-15-dependent Treg response in skin injury and promote resolution of skin inflammation

Mucosal-associated invariant T (MAIT) cells are enriched at barrier sites, but their role in autoimmune skin inflammation remains unknown. Using cutaneous lupus as a model, we identify MAIT cells as protective regulators of skin inflammation and as critical upstream modulators of regulatory T cells (Treg). Topical MAIT cell activation with 5-OP-RU induced durable resolution of spontaneous skin lesions in MRL/lpr mice and suppressed TLR7-driven skin inflammation. MAIT cell activation selectively expanded and activated Treg populations in both healthy and lupus-like skin, while suppressing effector T cell cytokine production and cytotoxic programs. This MAIT-Treg axis was also activated in UV light-driven barrier injury in healthy murine and human skin, where MAIT cells were required for UV-elicited Treg expansion and function. In lupus-like skin, local MAIT cell activation restored the defective UVB-induced Treg response and limited CD8+ T cell expansion. Mechanistically, CCR2+ monocyte-derived antigen-presenting cells and IL-15 signaling were required for MAIT cell-driven Treg accumulation and therapeutic benefits of MAIT cells in inflamed skin. These studies identify a MAIT-IL-15-Treg axis that links barrier injury sensing to immune regulation, which is disrupted in cutaneous lupus, and nominate therapeutic MAIT cell activation as an unappreciated strategy for restoring immune homeostasis in inflamed skin.

immunology↗

bioRxiv2026

Ketogenic diet synergistic reprogramming of both host and microbiome promotes tissue regeneration

Nutrition influences host physiological processes, yet how diets reshape host physiology, microbial functions, or host-microbe interactions to promote regeneration remains poorly explored. Here, we show that a ketogenic diet (KD), enriched in fats and low in carbohydrates, reprograms both skin microbial and immune functions to promote tissue repair. KD enhances IL-17A activity in {gamma}{delta} T cells and mucosal-associated invariant T (MAIT) cells, accelerating tissue repair, while KD-induced skin lipidomic alterations enhance both the abundance and metabolic output of Staphylococcus epidermidis. Metatranscriptomic and lipidomic analyses revealed increased riboflavin biosynthesis and sphingomyelinase (Sph)-dependent ceramide production in S. epidermidis under KD conditions. Genetic depletion of microbial ribD, a key enzyme for riboflavin biosynthesis, or of sph compromised the ability of the bacteria to promote tissue repair. Thus, host nutritional status drives tissue regeneration by synergistically rewiring host and microbial functions, providing new insights into how diet can be harnessed to regulate host physiology.

immunology↗

bioRxiv2025

MAIT cell responses to intracellular and extracellular pathogens are mediated by distinct antigen presenting cells

Mucosal-associated invariant T (MAIT) cells recognize microbial derivatives of riboflavin synthesis presented by the MHC class I-related (MR1) molecule. Although these metabolites are highly conserved among bacteria, the cells that present them remain unknown. Here, we show type-17 MAIT cells respond to diverse isolates of the extracellular pathogen Acinetobacter baumannii and promote bacterial clearance. Both hematopoietic and non-hematopoietic cells mediate MR1 presentation within the lungs and mediastinal lymph nodes (meLNs). Conversely, the type-1 MAIT cell response to the intracellular pathogen Francisella tularensis requires MR1 presentation by type-2 conventional dendritic cells (cDC2s) within meLNs and ablation of these cells or their expression of MR1 renders animals more susceptible to the infection. Although MR1 is broadly expressed at homeostasis, A. baumannii enhances MR1 on macrophages and fibroblasts, while F. tularensis increases expression on cDC2s. These results demonstrate that microbial tropism dictates which APCs mediate MR1 presentation of metabolites, revealing alternative therapeutic approaches.

immunology↗

bioRxiv2024

Antibiotic use in early life subsequently impairs MAIT cell-mediated immunity

Mucosal-associated invariant T (MAIT) cells are predominantly located in barrier tissues where they rapidly respond to pathogens and commensals by recognizing microbial derivatives of riboflavin synthesis. Early-life exposure to these metabolites imprints the abundance of MAIT cells within tissues, so we hypothesized that antibiotic use during this period may abrogate their development. We identified antibiotics that deplete riboflavin-synthesizing commensals and revealed an early period of susceptibility during which antibiotic administration impaired MAIT cell development. The reduction in MAIT cell abundance rendered mice more susceptible to pneumonia, while MAIT cell-deficient mice were unaffected by early-life antibiotics. Concomitant administration of a riboflavin-synthesizing commensal during antibiotic treatment was sufficient to restore MAIT cell development and immunity. Our work demonstrates that transient depletion of riboflavin-synthesizing commensals in early life can adversely affect responses to subsequent infections.

immunology↗