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Related to this point above, the development of Tregs and Teffs requires different metabolic checkpoints. Inhibition of cholesterol trafficking in T cells has been shown to inhibit mTOR activity. This is in agreement with a report showing that STAT5 phosphorylation was inhibited by depletion of intracellular cholesterol in erythroid progenitors The lower the ABCG1 expression in Tregs in human subjects, the higher the Treg frequency, thus supporting our findings in the mouse models.

These data suggest that polymorphisms that impact ABCG1 expression may play a role in regulating atherosclerosis and Treg numbers. It would be interesting for future studies to address whether there is a negative relationship between ABCG1 expression in Tregs and the extent of atherosclerosis in humans. In summary, our results show that Treg differentiation is preferentially increased by the accumulation of cholesterol.

This is the first direct evidence to our knowledge that intracellular cholesterol homeostasis affects Treg development.


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The increase in Treg numbers due to ABCG1 deficiency was sufficient to significantly reduce atherogenesis in mice. We also report here a similar inverse association between ABCG1 expression and Treg frequencies in a small-scale human study. Additionally, our study provides further clues supporting the notion that the manipulation of cholesterol content in T cells can control their signaling and fates.

All mice used were 8- to week-old females. For atherosclerosis studies, mice were fed a high-cholesterol diet containing 1. Mice were housed in microisolator cages in a pathogen-free animal facility at the La Jolla Institute for Allergy and Immunology. Flow cytometry. For evaluation of apoptosis, after surface marker staining, cells were stained with Alexa Fluor —conjugated annexin V dilution; Life Technologies, Thermo Fisher Scientific for 15 minutes at room temperature and washed twice. The samples were analyzed immediately after staining.

Phospho-flow cytometry. Immediately following stimulation, cells were stained with surface stain on ice, followed by fixation and permeabilization and staining for FOXP3 and phosphorylated proteins. In vivo proliferation assay. Mice were injected i. Bone marrow chimera generation. Recipient CD Bone marrow cells from both femurs and tibiae of B6. Bones were centrifuged for the collection of marrow, and the cells were washed and resuspended in PBS for injection. Bone marrow cells from B6. SJL CD The ratio of the bone marrow cells was confirmed by flow cytometry.

Ten weeks after the injection, the T cell composition of the chimeric mice was analyzed by flow cytometry. Atherosclerosis quantification. Mouse aortae were collected and immersed in paraformaldehyde and stained with oil red O, opened longitudinally, and pinned Images were scanned, and the percentage of surface areas occupied by lesions was determined with ImageJ software NIH.

In vitro Treg differentiation. Four days later, cells were removed from beads, stained for Treg markers, and analyzed by flow cytometry. Adoptive transfer. The ratio of naive CD4 cells was confirmed by flow cytometry. Ten days after the injection, the T cell composition of the recipient mice was analyzed by flow cytometry. Treg suppression assay.

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Labeled naive T cells 1. Cell division of naive T cells was quantified as CellTrace Violet dilution by flow cytometry. Threshold cycles Ct were determined by an in-program algorithm assigning a fluorescence baseline based on readings prior to exponential amplification. Human blood analysis. Twenty-five human blood samples were collected at the University of Virginia Cardiac Catheterization Laboratory.

Enrolled research participants included both men and women, aged 40—80 years, who presented for a medically necessary cardiac catheterization 15 men and 10 women, average age of Blood was drawn into tubes containing EDTA. HPRT1 was used as an endogenous control. Plasma lipoprotein measurements.

Introduction

Plasma cholesterol and triglycerides were measured using fast protein liquid chromatography FPLC as described previously 16 , 51 , Lipoproteins were eluted by size exclusion into 0. A P value of less than 0. Linear regression was used to determine the strength of association between Treg percentages and ABCG1 expression in the human study. An R value between —0. Study approval. It occupies significant number of genes, which are direct targets of Foxp3 and thus, collaborates with Foxp3 to establish Treg gene expression program.

Indeed, Treg-specific GATA3 deletion results in intestinal pathology with heightened Th2 cytokine production from large intestinal effector T-cells However, these cells have substantially reduced CpG methylation within the CNS2 enhancer region of Foxp3 locus, which is known to be well correlated with stable Foxp3 expression , Mechanistic insights on why certain bacteria have superior capacity of inducing intestinal Tregs than others have started to emerge only recently. It has been reported that short chain fatty acids produced upon fermentation of starch and other dietary fibers by clostridia strains, mainly butyrate and propionate but not acetate, can contribute to colonic Treg generation.

Mechanistically, this is attributed to their histone deacetylase inhibitory properties resulting in increased acetylation of Foxp3 locus , Figure 3. Apart from directly acting on T-cells, butyrate also affects DC ability to induce Treg differentiation. Indeed, in vitro treatment with butyrate represses lipopolysachharide response genes, including Il12, Il6 , and Relb in DCs Figure 3. On a translational note, in human IBD patients, colonic butyrate producing bacteria are decreased and mucosal butyrate transporter, monocarboxylate transporter 1, is downregulated It is also possible that colonic Tregs are generated in an antigen-specific manner.

Indeed, colonic Treg TCRs have been reported to interact with colonic bacteria in vitro Very recently, colonic T cells with TCRs cognate to epitopes of a pathobiont Helicobacter hepaticus are shown to induce pTregs under homeostatic conditions This study establishes the role of colonic pTregs in induction and maintenance of tolerance to pathobionts as well.

Most of these cells express low levels of Nrp1 and thus are, supposedly, pTregs. Their localization suggests that these are primarily generated against dietary antigens. It appears that Amphiregulin mediated tissue repair might be a generalized mechanism employed by tissue-resident Tregs as exemplified by its evolving role in lung resident as well as intratumoral Tregs , Of note, one more function of siTregs was identified recently while looking at the IEL population.

It was observed that LP Tregs migrate to epithelial compartment as well, where a fraction of them lose Foxp3 expression IELs have cytotoxic as well as immunoregulatory machinery suggesting a role in both mucosal barrier maintenance and elimination of stressed intestinal epithelial cells Being our exterior, it is always exposed to environmental, microbial, physical, and chemical insults.

Anatomically, skin is composed of three layers, the outer epidermis, middle dermis, and inner subcutaneous tissue layer The terminally differentiated keratinocytes in epidermis synthesize long, thread-like protective protein keratin and form a physical barrier. Products of various sweat and sebaceous glands interspersed at epidermal—dermal junction along with antimicrobial peptides develop an acidic hydrophilic skin which acts as a biochemical barrier The epidermal—dermal junction also hosts hair follicles.

Cellular component of epidermis comprises of Langerhans cells specialized skin DCs and T lymphocytes. Understandably, given the exposed nature of skin, it is highly vulnerable to overzealous immune responses against skin commensals and self-antigens. Tregs are an important component of establishing tolerance and homeostasis in the skin.

Indeed, both scurfy mouse and human IPEX patients present fulminating immune responses in skin. It is difficult to establish the origin of cutaneous Tregs, given the paucity of specific information. However, a wave of Tregs has been shown to populate the skin in early neonatal period in a skin bacterial colonization model in mice Furthermore, restricting lymphoid emigration of T-cells by treating with sphingosinephosphate receptor antagonist FTY resulted in preferential accumulation of Tregs in thymus instead of skin draining LNs, suggesting their migration directly from thymus This is little surprising as skin Tregs establish tolerance to not only self-antigens but also to commensals.

How are then commensal antigen-specific Tregs generated in thymus? One possibility appears to be plasmacytoid DCs pDCs that have been shown to be able to take up innocuous peripheral antigens to thymus and LNs to induce tolerance. Generally, pDCs are not present in skin but can accumulate in the presence of inflammatory conditions , Another probability is that some tTregs have TCRs with sufficient cross-reactivity to microbial antigens and thus can specifically expand and accumulate at sites where antigen is present. However, if indeed skin Tregs are thymic by origin, the concerning mechanisms remain to be elucidated.

Modeling of inducible expression of a self-antigen, by fusing transferrin receptor transmembrane domain, GFP and amino acids — of chicken ovalbumin in mouse epidermis, revealed that circulating Tregs are not able to suppress primary immune response against OVA, though it initiated activation of Tregs The inflammation resolved spontaneously and any subsequent antigen expression led to an attenuated and short immune response. It is to be noted here that a recent study examining the transcriptional, epigenomic, and functional changes in inflammation experienced Tregs employing the Foxp3 DTR system, presented that Tregs revert most of the activation induced changes and lose the accentuated suppressive ability over time In a mixed bone marrow chimera study, CCR4-deficient Tregs could not reconstitute the skin Treg compartment These molecules sequentially manage T-cell homing to skin, where CCL17 promotes vascular recognition and extravasation and CCL22 guides subsequent migration in skin Since skin is heavily exposed to commensals as well as pathogens, it is imperative to speculate that a fine tuning of effector and suppressive immune responses has evolved.

The commensal microbiota residing within skin has been shown to calibrate barrier immunity , To identify mechanisms behind development of tolerance to skin commensals, Scharschmidt et al. Surprisingly, skin colonization in adult mice did not evoke any tolerance to bacteria, as seen by inflammatory response upon re-challenge. However, when neonatal mice were colonized for a week during postnatal week 2, there was an appreciable attenuation of inflammatory response upon re-challenge after 3—4 weeks.

Subdued response was associated with marked enrichment of antigen-specific Tregs in skin and draining LNs and the tolerance could be reversed upon FTY treatment Another study has also shown that Tregs, generated very early in life in a defined perinatal window, play a very distinct role in maintaining self-tolerance Thus, in mice, an abrupt wave of Treg infiltration occurs in a defined early postnatal period to establish dominant tolerance toward skin commensals Figure 5.

Figure 5. Cutaneous regulatory T-cells Tregs facilitate hair morphogenesis and establish tolerance to skin commensals. Skin Tregs colonize mouse skin in early postnatal period coinciding with initial microbial colonization and hair follicle development. Skin microbes enter the hair follicle which induces production of chemokine CCL20 from infundibular cells that attracts large number of Tregs expressing corresponding receptor CCR6.

The accumulated Tregs subsequently establish tolerance to these commensals. Also, during the resting phase of hair growth telogen which initially coincides with commensal entry in hair follicle, large number of Tregs are seen in contact with hair follicle stem cells HFSCs in the bulb of follicle. These Tregs provide notch ligand Jagged1 to the stem cells. Notch signaling triggers the active phase of hair growth cycle anagen. Tregs are reduced in anagen phase around HFSCs. Both Tregs and skin commensals are localized to hair follicles and in mouse, the time of Treg infiltration week 2 postnatal is coincident with hair follicle development , Thus, it was speculated that hair follicles might have a role in ingress of Tregs in skin.

It has been shown that chemokines from different parts of hair follicles like CCL2 from isthmus, CCL20 from infundibulum, and CCL8 from bulge keratinocytes generate specific type of Langerhans cells Similarly, in a mouse model of skin specific hair follicle morphogenesis arrest, skin Treg population was reduced without affecting Treg population in intestine or draining LNs in neonatal mice It was confirmed by adoptive transfer experiments that CCR6-deficient Tregs were at a competitive disadvantage to reconstitute skin T-cell compartment CCL20 mRNA expression also increases in human fetal skin explants upon exposure to cutaneous commensals and bacterial components Thus, tissue morphogenesis hair follicle generation and subsequent chemokine production by the cells of hair follicle and commensals are shown to cooperate in developing a tissue-specific immune tolerance.

It would be interesting to extrapolate this model to other microbe inhabited organ systems. Whether, these mechanisms sustain throughout the life span particularly in adult life is not known. It is possible that yet unknown factors other than commensals increase Treg population in adult GF skin or a lack of tuned immune response against commensals diverts immune resources toward self-antigens and in turn, progressively enrich self-antigen-specific Tregs in skin. Interestingly, UVB phototherapy is an effective treatment in autoimmune skin conditions, like psoriasis and atopic dermatitis Figure 6.

Cutaneous regulatory T-cells Tregs actively repair skin tissue damage. CCL17 is secreted by endothelial cells in inflamed skin and helps in extravasation of Tregs, CCL22 manages subsequent migration of Tregs. These DCs are suppressed by Tregs which have high surface expression of CD and P-lig and thus can migrate into non-inflamed skin as well, subsequent to UV exposure. True to the nature of tissue-resident Tregs where they have been shown to not only develop immune tolerance but also get accustomed to and help local physiology, cutaneous Tregs in hair follicles have been found to modulate hair follicle stem cells HFSCs in addition to establishing tolerance to commensals.

In mouse skin, an abundance of Tregs was found during telogen phase of hair follicle growth which is characterized by quiescence only to be followed by an active proliferation phase called anagen. Treg population decreases during anagen phase. And as these phases alternate in mouse skin so are the numbers of hair follicle associated Tregs Figure 5. Animals with transient depletion of Tregs during telogen, failed to progress to anagen phase and could not re-grow hairs Akin to Tregs in hematopoietic system which form an immune-privileged site to provide a protective niche to hematopoietic stem cells , hair follicle Tregs were found to co-localize with HFSCs.

Regulatory T-cells play an important role in cutaneous wound healing as well. They accumulate in large numbers at the site soon after a wound injury in skin The Tregs involved in cutaneous wound healing were shown to be dependent on EGFR pathway as in lung and muscle-healing Tregs , , Figure 6. Tumors are wounds that do not heal — Solid tumors, in particular, heterogeneously indulge in various stages of wound healing, which provide essential growth factors for the tumor growth.

How tolerogenic dendritic cells induce regulatory T cells.

This hijack of natural processes results in heightened inflammation and its subsequent resolution in the tumor microenvironment, presumably setting up a vicious cycle. Inflammation on one hand provides growth and metastasis opportunities; resolution of inflammation helps the tumor to escape antitumor immunity. For most of the tumors, the presence of high number of Tregs indicates a guarded to grave prognosis.

As tTregs and pTregs differ in their stability, conclusive information about origin of TI-Tregs can be very valuable to design TI-Treg specific therapies in cancers. Tumors drive immune responses against tumor-associated self-antigens as well as tumor-specific neo-self antigens. Thus, in theory, Tregs against self-antigens tTregs and pTregs against neo-self antigens are possible.

Regulatory T cells

However, TI-Tregs in several murine tumors have been shown to express high levels of Nrp1 and Helios proteins, suggestive of a thymic origin Further, these studies confirmed that there is enrichment and expansion of selective TCR bearing Tregs inside tumor microenvironment , Malchow et al. They found that Tregs expressing a single TCR MJ23 , reactive to a normally expressed prostate antigen, consistently populated the tumors This TCR was able to drive a tTreg clone development. However, a deficiency of the transcription factor autoimmune regulator abolished development of these clones , suggesting that at least in these experimental settings, TI-Tregs are generated in thymus against a normal tissue expressed self-antigen Figure 7 A.

Both of these ligands are non-overlapping peptides originating from same prostatic protein Tcaf3 and while one is expressed in mouse prostate tumors MJ23 , the other is associated with prostatic autoimmune lesions SP33 Another study focusing on epigenetic hallmarks of tTregs found that TI-Tregs had consistently hypomethylated Foxp3 CNS2 in various orthotopic and heterotopic transplanted tumor models, even at different time points of tumor growth These findings were further confirmed in TI-Tregs from different human tumors.

It is to be noted that there have been equivocal reports about the demethylated CNS2 being specific for tTregs, since Foxp3 CNS2 region in pTregs has also been shown to be demethylated , , most likely upon eventual stabilization following its de novo induction. Figure 7. Origin, accumulation, and functional potentiation of tumor-infiltrating regulatory T-cells Tregs. A Tumor-specific antigens can be expressed by thymic epithelial cells in an Aire -dependent manner, which then select the tumor antigen-specific Tregs.

Tregs can also be directly recruited to tumors and undergo expansion there. While intratumoral conversion of effector T-cells to pTregs is likely, the extent to which this occurs under physiological conditions is not completely understood. Further, Tregs also produce Amphiregulin in certain tumor types, which help in tumor progression. Overall, available evidences largely point toward higher enrichment and expansion of tTregs inside solid tumors. Probably more conclusive lineage tracing experiments across tumors can be proven more insightful. Recent studies analyzing transcriptome of TI-Tregs from human cancers have identified that though TI-Tregs are largely similar to normal tissue-resident Tregs, these have some specific characteristics and molecular patterns which can be utilized for selective therapy , , Plitas et al.

Recently, BATF was shown to be involved in context dependent gene set expression in tissue Tregs These genes are significant in converting cTregs to eTregs, therefore, their decreased expression led to a widespread tissue-specific autoimmunity It is possible that CCR8 is expressed to retain Tregs in tumors. Whether, CCR8 expression is an indicator of highly suppressive TI-Tregs or it has further functional importance is not yet known. Such cells, subsequently, upregulate their expression of FOXP3, CD39, Granzyme B, and IL10 and are functionally more suppressive in a microsuppression assay and in a mouse model of multiple sclerosis There is a repertoire of known and yet unknown mechanisms which Tregs utilize to suppress an immune response.

However, how the TI-Tregs have highly accentuated suppressive response is not very well understood. A large accumulation of Tregs might help in a collective exaggerated suppression, but it cannot explain individual potentiation. Recently, it was shown that TI-Tregs are highly apoptotic on account of comparatively low expression of the transcription factor Nuclear factor like 2 NRF2 NRF2 regulates antioxidant defense system in macrophages and epithelial cells It is to be noted though that earlier Imatinib induced apoptosis of TI-Tregs was shown to enhance antitumor immunity Binding of Nrp1 to its ligand Semaphorin4a increased Foxo1 and Foxo3 nuclear localization by inhibiting AKT phosphorylation which stabilized Treg signature genes and antiapoptotic genes Figure 7 C.

This observation emphasizes that Tregs can not only modulate other immune cells but can phenotypically influence other Tregs as well. However, as most of the solid tumors become progressively hypoxic , , whether this phenomenon is prevalent in progressive tumors and if so, whether it is efficient for a significant regeneration of antitumor immune response, remains to be seen.

Overall, these findings suggest that there is a specific phenotypic and functional identity to TI-Tregs and thus, it is possible to selectively target them for triggering efficient antitumor immunity. As the diversity in characteristics and functions of tissue Tregs is being unraveled, several other interesting populations have been described which deserve more detailed phenotypic and functional characterization. It was reported earlier that in a non-inflammatory model of regenerative alveologenesis, Tregs enhanced epithelial proliferation.

In accordance to these findings, a distinct population of Tregs expressing high levels of pro-inflammatory cytokine IL18 receptor IL18R and ST2 has been described in lungs In animals with Treg specific amphiregulin deficiency, a rapid decline in lung functions was observed upon intranasal influenza virus infection, while antiviral immune response was intact Figure 8. Emerging evidences highlight a compulsory requirement of regulatory T-cells Tregs in tissue regeneration and repair.

A Both lungs and muscles contain population of Tregs which proliferate vigorously upon tissue injury. Muscle Tregs respond to IL33 produced upon muscle damage and produce amphiregulin for subsequent repair. B In zebrafish, mammalian Foxp3 ortholog Foxp3a expressing Tregs zTregs are primarily present in kidney. However, upon tissue injury, they soon accumulate at the site of the injury. Another unique tissue Treg population has been found in skeletal muscles, where by virtue of amphiregulin secretion, they help in muscle regeneration and healing.

How tolerogenic dendritic cells induce regulatory T cells.

High expression of Nrp1 and Helios and a unique and restricted TCR repertoire suggests thymic origin of muscle Tregs and reactivity to a local muscle antigen These Tregs have a unique transcriptome compared to lymphoid organ Tregs with several differentially expressed genes. They have upregulated transcripts involved in Treg mediated suppression Il10, Gzmb , etc. Depletion of Tregs during a muscle injury episode delays muscle healing, most probably because of loss of Treg generated amphiregulin.

Thus, muscle Tregs seem to be involved in an alarmin induced repair process Figure 8 A. Interestingly, muscle Treg population declines in old age mice which results in a deterioration of repair and regeneration process Recently, a very elegant and detailed study in zebrafish has elaborated upon yet unknown and spectacular regenerative capabilities of Tregs Figure 8 B.

The authors found that an ortholog of mammalian Foxp3, Foxp3a , which was exclusively expressed in a subpopulation of zebrafish T-cells, was upregulated most prominently in distinct regenerating organs. Zebra fish Tregs zTregs were predominantly found in kidneys but infiltrated and vigorously proliferated in regenerating tissues. As in the mammalian counterparts, these cells expressed high levels of Nrp1a and Helios in comparison to kidney zTregs It has been reported that CNS1 region of Foxp3 locus, responsible for pTreg generation, is not found in zebrafish Deletion of zTregs, in fact, reduced the tissue-specific precursor cells and subdued their proliferation Indeed, zTregs were found near progenitors, sometimes even in close contact That zTregs are the primary source of these growth factors was confirmed by rescue of regeneration in zTreg depleted tissues by recombinant tissue-specific growth factors The regeneration potential of zTregs was independent of their immunosuppressive potential or at least was not dependent on their IL10 production as ILdeficient cells were fully capable of inducing precursor cell proliferation.

On the other hand, Areg expression was not Foxp3a dependent and its role in regeneration was limited. It would be interesting to extrapolate and confirm similar findings in murine and human tissues. An equally fascinating population of Tregs which accumulates in murine placenta to induce maternal tolerance to fetus has been described To say that the Tregs are extremely important from the outset of pregnancy will not be an overshoot [reviewed in Ref. Women with recurrent spontaneous abortions have reduced Treg population Apart from the their most likely peripheral origin, it is not known whether these Tregs have a distinct phenotypic and functional profile, elucidation of which could come very informative toward amelioration of infertility, pre-eclampsia, and other spontaneous abortive disorders.

Very recently, an elegant study on human fetal antigen presenting cells has found that fetal counterparts of DCs are primarily tolerogenic in their response. And, the primary response is generation of Tregs, even more than the adult DCs, in an in vitro Treg differentiation assay These DCs were found across several fetal tissues, including spleen, thymus, skin, gut, and lungs Unfortunately, the authors did not describe if Tregs were also present in these tissues.

Earlier, it has been shown that human fetal Tregs promote tolerance to non-inherited maternal antigens but only recently, it came to light that Tregs are required for suppression of in utero autoimmunity as well. Two children with IPEX syndrome, who died soon after birth, presented histological evidences of tertiary lymphoid structures, chronic inflammatory changes, and targeted exocrine pancreas autoimmunity This signifies that in the perplexing settings of a pregnancy, Tregs are instrumental in establishing tolerance at both ends of maternal—fetal relationship.

Translational utility of many biological processes is marred by lack of specificity. A similar dilemma exists for Treg biologists as well; however, in case of Tregs selective therapeutic targeting appears to be achievable by virtue of harnessing their gradually established phenotypic and functional diversity. While in testis, where otherwise privileged autoantigen escapes from the seminiferous tubules, only to generate systemic tolerance via Tregs , the retina actively recruits Tregs, which not only attenuate inflammation, but also repair the vasculature, saving blinding neovascular retinopathies Another layer of specificity is added by discovery of tissue-resident Tregs and their unique characteristics.

However, most of the information except the recent reports on skin resident Tregs and TI-Tregs are from mouse tissues. There are several differences in structure as well as physiology between mice and humans. For example, mouse skin contains a thin muscle layer panniculus carnosus , which is vestigial in humans This helps in contraction, revascularization and healing of wounds without scar formation in mouse.

Human skin on the other hand heals by secondary intention leaving scar tissues. Thus, it is important to identify human tissue Tregs for an informed effort toward therapeutic usage.

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There is a need to conclusively establish the origin and accumulating factors for tissue Tregs. One of the most pressing questions about almost all the tissue Tregs is identification of their natural ligands or tissue antigens. Although it has been demonstrated that in certain cases Tregs do not need TCR stimulation for some of their functions , Tregs with a smaller subset of specific TCR repertoire populate various tissues as well as malignancies.

Therefore, cognate ligands that help in survival and proliferation of Tregs in these tissues are likely to have significant contributions in catering tissue-specific modulations. Proof of concept studies provide evidence that Tregs with defined antigen specificity chimeric antigen receptor Tregs, CAR-Tregs have potent immunosuppressive functions along with advantage of not inducing generalized immunosuppression Question remains as to how Tregs communicate with specific tissue cells-like adipocytes to establish a channel of communication with the environment.

Beyond adaptation to inflammatory context, there are peculiarities of Treg biology, which modulate their effect temporally in life as well. The mechanisms that drive such specific outcomes need to be studied in detail. This accentuated capability to adapt sometimes becomes counterproductive too as seen in tumors where the suppressive capacity is enhanced even in comparison to normal tissue-resident Tregs and is, in turn, utilized by tumors for their survival and immune escape.

The mechanisms by which Tregs can push the limits of their functional capabilities are yet to be identified. A major aspect of tissue adaptation is adjusting the cellular metabolism according to the tissue environment. There are huge gaps in our understanding of both lymphoid and tissue Treg metabolism. In in vitro differentiated Tregs iTregs , it was shown that Foxp3 suppresses glycolysis by repression of Myc and helps in developing resistance to l -lactate Contrastingly, splenic and TI-Tregs were shown to uptake more 2NBDG, a fluorescent glucose analog, while intratumoral effector T cells showed glucose deprivation leading to reduced production of glycolytic metabolite phosphoenol pyruvate, resulting in compromised effector functions via reduced calcium-NFAT signaling More recently, glycolysis was found to be instrumental in Treg trafficking and migration to inflamed tissues.

The induction of the glycolytic enzyme glucokinase GCK and cytoskeletal rearrangement upon its association with actin was shown to be critical for the process These findings underscore the need for extensive studies to delineate metabolic reprogramming in not only tissue Tregs but also lymphoid Tregs under steady state and activated conditions.

One can only be amazed by the diversity and functional plasticity of Tregs. A question, therefore, always comes up as to why Tregs are the chosen ones? Whether similar diversities among other immune cell types are still awaiting discoveries, or whether Foxp3 and presumably other unknown factors provide some degree of functional uniqueness to Tregs, remains to be seen.

T-Cell Tolerance: Central and Peripheral

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Sunderland, MA: Sinauer Associates Google Scholar. Towards a liquid self: how time, geography, and life experiences reshape the biological identity. Front Immunol Immune tolerance for autoimmune disease and cell transplantation.

Annu Rev Biomed Eng — Steinman RM. Decisions about dendritic cells: past, present, and future. Annu Rev Immunol — Lewis KL, Reizis B. Dendritic cells: arbiters of immunity and immunological tolerance. Cold Spring Harb Perspect Biol 4 8 :a Liu J, Cao X. Regulatory dendritic cells in autoimmunity: a comprehensive review. J Autoimmun — Mauri C, Menon M.

Human regulatory B cells in health and disease: therapeutic potential. J Clin Invest 3 —9. Regulatory B cells in infectious disease review. Mol Med Rep 16 1 :3— Regulatory innate lymphoid cells control innate intestinal inflammation. Cell 1 — Tr1-like T cells — an enigmatic regulatory T cell lineage. Wing JB, Sakaguchi S. Int Immunol 26 2 —9. The regulation of immune tolerance by FOXP3.

Nat Rev Immunol 17 11 — Regulatory T cells: mechanisms of differentiation and function.


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Xing Y, Hogquist KA. T-cell tolerance: central and peripheral. Cold Spring Harb Perspect Biol 4 6 :1— Surh CD, Sprent J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature —3. T-cell receptor affinity in thymic development. Immunology 4 —7. Nemazee D. Receptor editing in lymphocyte development and central tolerance. Nat Rev Immunol 6 10 — Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease.

Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains CD Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 3 — PubMed Abstract Google Scholar. Nishizuka Y, Sakakura T. Ovarian dysgenesis induced by neonatal thymectomy in the mouse. Endocrinology 89 3 — Autoimmune oophoritis in thymectomized mice: detection of circulating antibodies against oocytes. Clin Exp Immunol 40 3 — Taguchi O, Nishizuka Y. Experimental autoimmune orchitis after neonatal thymectomy in the mouse.

Clin Exp Immunol 46 2 — Spontaneous development of autoimmune thyroiditis in neonatally thymectomized mice. Lab Invest 34 6 —7. Experimental production of possible autoimmune castritis followed by macrocytic anemia in athymic nude mice. Lab Invest 42 4 — Kojima A, Prehn RT. Genetic susceptibility to post-thymectomy autoimmune diseases in mice. Immunogenetics 14 1—2 — Thyroiditis in T cell-depleted rats: suppression of the autoallergic response by reconstitution with normal lymphoid cells. Clin Exp Immunol 25 1 :6— Organ-specific autoimmune diseases induced in mice by elimination of T cell subset.

Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J Exp Med 1 — B scid mice. Int Immunol 5 11 — Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 2 — Shevach EM. Fatal lymphoreticular disease in the scurfy sf mouse requires T cells that mature in a sf thymic environment: potential model for thymic education.

J Immunol 8 — Disease in the scurfy sf mouse is associated with overexpression of cytokine genes. Eur J Immunol 26 1 —5. The murine mutation scurfy sf results in an antigen-dependent lymphoproliferative disease with altered T cell sensitivity. Eur J Immunol 31 1 — Immunity 3 5 —7. Thus thymic selection mechanisms operate to shape the T-cell repertoire. Thymocytes that have a TCR with low affinity for self-peptide—MHC complexes are positively selected to further differentiate and function in adaptive immunity, whereas useless ones die by neglect.

Clonal deletion and clonal diversion Treg differentiation are the major processes in the thymus that eliminate or control self-reactive T cells. Although these processes are thought to be efficient, they fail to control self-reactivity in all circumstances. Thus, peripheral tolerance processes exist wherein self-reactive T cells become functionally unresponsive anergy or are deleted after encountering self-antigens outside of the thymus.

Recent advances in mechanistic studies of central and peripheral T-cell tolerance are promoting the development of therapeutic strategies to treat autoimmune disease and cancer and improve transplantation outcome. Abstract Somatic recombination of TCR genes in immature thymocytes results in some cells with useful TCR specificities, but also many with useless or potentially self-reactive specificities. Also in this Collection. This Article doi: