In a recent study published in Immunology, researchers investigated populations of regulatory T cells (Treg), a type of white blood cell, in various tissues.
Researchers at the University of Cambridge have identified that regulatory T cells exist as a large, mobile population that continuously travels through the body to locate and repair damaged tissue.
Background
Immune reactions take place in tissues; however, the ways in which the components of the immune system regulate these reactions are unclear. Regulatory T cells usually reside in lymphoid organs in the human body; recent research has identified their presence in non-lymphoid tissues.
Regulatory T cells contribute to physiological homeostasis. These cells improve insulin sensitivity and lipid breakdown in fatty tissues, improve muscle repair, and promote cell differentiation in the brain. Moreover, regulatory T cells prevent skin fibrosis and support intrauterine fetal growth. The immunological implications of regulatory T cells across different tissue types warrant further research.
About the study
The present study explored regulatory T lymphocyte populations in non-lymphoid, lymphoid, and intestinal tissues, testing the seeding and specialization model.
The researchers examined Treg populations across 48 murine tissues and used flow cytometry to assess Treg phenotypes. They investigated markers associated with the activation and residency of regulatory T cells. They assessed vascular-exposed regulatory T populations using antibodies against the cluster of differentiation 45 (CD45).
The researchers explored the effects of age, biological sex, and microbiome on the tissue Treg niche and phenotype. They evaluated the impact of microbes on tissue Tregs by comparing the standard pathogen-free (SPF) mice to gnotobiotic and microbial re-wilded mice. They performed transcriptomic analyses of regulatory T cells obtained from blood, lymphoid organs, intestinal tissues [lamina propria leukocyte (LPL) and intestinal epithelium leukocyte (IEL)], and other tissues.
The researchers conducted a multi-point parabiotic experiment, wherein CD45.1 mice were parabiosed to CD45.2 animals to measure cell displacement. They quantified dwell times using probabilistic Markov chain modeling and Bayesian analysis. They used recombined T-cell receptors (TCR) as clonal barcodes to investigate clonal sharing among non-lymphoid tissue types.
The researchers sequenced Tregs from mice, emphasizing blood and non-lymphoid populations such as the pancreas, kidney, LPL, and liver. They also performed parabiosis and tissue-transfer experiments, comparing the repopulation of the female reproductive tract in donor-experienced and donor-naive parabionts and injecting Tregs collected from various tissues into Rag-deficient animals.
Results
Non-lymphoid and non-intestinal tissues exhibited Treg phenotypes with similar TCR clonality and genetic requirements. After three weeks in tissues, Tregs become tissue-indifferent upon re-entry. With modifications specific to particular tissues, they progressively seep through them. In non-lymphoid tissue types, Treg cells expressed suppression of tumorigenicity 2 (ST2+), killer-cell lectin-like receptor G1 (KLRG1+), and CD69. Regulatory T cells are distributed in various tissues and exhibit strong phenotypic homology with non-intestinal and non-lymphoid tissues.
The Treg vascular component bridged between the blood and the CD45-tissue compartment. Except for muscles and white adipose tissues, where Tregs were more numerous due to inflammation, Treg counts were generally steady across ages. Age-related phenotypic adaptations were more pronounced, with mild increases in Treg numbers linked to increased microbial complexity. The team noted higher Treg counts in female salivary glands and male adipose tissues.
While transcriptome profiles of intestinal and non-lymphoid Tregs were comparable, intestinal Tregs distinctly showed increased C-C chemokine receptor type 5 (CCR5) and CCR9 expression and lower Homo sapiens selectin L (SELL) and Integrin beta1 (ITGB1) expression. Residency genes negligibly impacted Treg counts; basic-type leucine zipper transcription factor, ATF-like (BATF), CD11a, and CD69 deficiency decreased Treg populations. Most members’ expressions varied between tissues rather than being tissue-specific, depending on the other members.
All tissues showed short modeled dwell durations for resting and active Tregs, with CD69+ cells exhibiting the highest dwell times. High entrance rates drove the kinetics of lymphoid tissues, whereas very transitory resting or activated Treg cells indirectly seeded non-lymphoid tissue types. CD69+ Treg cells were directly introduced into non-lymphoid tissues by blood. Tregs could infiltrate non-lymphoid and gut tissues, indicating pan-tissue clonality.
Conclusion
Based on the study findings, one Treg pool seeds various tissues, and shared TCR sequences facilitate multi-tissue mobility. Age and microbial stress expand the Treg cellular niche while maintaining its phenotypic integrity. Tregs have similar residence-related genetic factors in addition to a shared phenotype.
The identical morphological and genetic characteristics of Tregs across tissues facilitate pan-tissue trafficking. Treg cells migrate into tissues, develop, reside temporarily, and leave. TCRs promote a pan-tissue migration and residency profile.
The study findings challenge the idea that specialist populations of regulatory T cells exist only in specific parts of the body. These findings have implications for the treatment of disease with more targeted drugs, with potentially rapid results.
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